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Abstract
Tacrolimus, also known as FK-506, is a potent immunosuppressant agent with a host of drug-drug and food-drug interactions. We present the first case of a probable food-drug interaction between the herb turmeric and tacrolimus leading to acute calcineurin inhibitor nephrotoxicity. A 56-year-old man with a history of orthotopic liver transplantation presented to the emergency department from the clinic with worsening edema in the setting of an elevated creatinine level of 4.2 mg/dL. Before the current presentation, the patient had been recently discharged on a previously tolerated low-dose regimen of tacrolimus with a whole-blood tacrolimus level within the desired range. Tacrolimus level on the day of re-hospitalization was elevated to 29.9 ng/mL in the absence of any changes to the patient's medication regimen. On further prompting, the patient identified recent high-dose intake of turmeric with his food. Tacrolimus was held from the patient's medication regimen, and he was discharged on hospital day 4 with objective evidence of improving renal function. Our report builds on the previous studies that described the effects of turmeric or its active ingredient on the pharmacokinetics of tacrolimus. The appropriate reconciliation of herbal agents such as turmeric can be worthwhile in patients with unexplained changes in tacrolimus levels.
... Similar effects can be observed after the intake of ginger, turmeric, green tea and pomegranate juice, during treatment with tacrolimus. Possibly, the mechanism of action may be the same and may involve the inhibition of intestinal CYP3A4 and P-gp [8,10,12,[16][17][18]. ...
... A study on rats revealed a significant growth in the AUC of tacrolimus when coadministered with ginger or turmeric [12]. Nayeri et al. [17] reported a case of acute calcineurin inhibitor nephrotoxicity caused by excessive turmeric intake. The patient had added over 15 spoons of turmeric to his meals daily, which resulted in a three-fold increase in blood tacrolimus level. ...
Tacrolimus is an immunosuppressive calcineurin inhibitor used to prevent rejection in allogeneic organ transplant recipients, such as kidney, liver, heart or lung. It is metabolized in the liver, involving the cytochrome P450 (CYP3A4) isoform CYP3A4, and is characterized by a narrow therapeutic window, dose-dependent toxicity and high inter-individual and intra-individual variability. In view of the abovementioned facts, the aim of the study is to present selected interactions between tacrolimus and the commonly used dietary supplements, herbs and food. The review was based on the available scientific literature found in the PubMed, Scopus and Cochrane databases. An increase in the serum concentration of tacrolimus can be caused by CYP3A4 inhibitors, such as grapefruit, pomelo, clementine, pomegranate, ginger and turmeric, revealing the side effects of this drug, particularly nephrotoxicity. In contrast, CYP3A4 inducers, such as St. John’s Wort, may result in a lack of therapeutic effect by reducing the drug concentration. Additionally, the use of Panax ginseng, green tea, Schisandra sphenanthera and melatonin in patients receiving tacrolimus is highly controversial. Therefore, since alternative medicine constitutes an attractive treatment option for patients, modern healthcare should emphasize the potential interactions between herbal medicines and synthetic drugs. In fact, each drug or herbal supplement should be reported by the patient to the physician (concordance) if it is taken in the course of immunosuppressive therapy, since it may affect the pharmacokinetic and pharmacodynamic parameters of other preparations.
Citation: Miedziaszczyk, M.; Bajon, A.; Jakielska, E.; Primke, M.; Sikora, J.; Skowrońska, D.; Idasiak-Piechocka, I. Controversial Interactions of Tacrolimus with Dietary Supplements, Herbs and Food.
... The possible reason for increasing BWG% might be due to increase in food intake. This effect was due to the presence of curcumin; the main ingredient of turmeric (Nayeri et al. 2017) which was due to the secretion of mucin which protect gastrointestinal tract against irritation and enhances intestinal lipase, sucrose and maltase activity ( Lee et al. 2003 andPlatel andSrinivasan 1996). Recently, Lee et al. (2016) confirmed that, supplementation of turmeric extract improved body weight gain in CCL4 treated rats. ...
... By inhibition of oxidative stress and formation of reactive oxygen species (Behrman et al. 2001). At the same subject, curcumin, the main ingredient of turmeric has medicinal properties that it has protective effect against liver disease (Nayeri et al. 2017) by decreasing expression of intestinal cytochrome P450 3A (Zang et al. 2007). ...
... These agents are substrates of cytochrome P450 3A4 (CYP3A4) and the multidrug transporter P-glycoprotein (P-gp) [92,93]. While existing studies in humans regarding drug interactions are limited, immunosuppressant drug levels may become supratherapeutic with concomitant use of CAM products which reportedly inhibit CYP3A4 and P-gp, including chamomile [94], green tea extract [95], and turmeric [96]. Conversely, the use of high hyperforin concentration SJW preparations may induce CYP3A4 and P-gp, consequently lowering serum levels of immunosuppressants and increasing the risk of rejection of the graft [97]. ...
Purpose of Review
Traditional, complementary, and integrative medicine (TCIM) modalities are widely employed. However, TCIM, specifically herbal and non-herbal dietary supplements, can pose challenges in the context of organ transplantation. In this review, we discuss common supplements used for psychiatric purposes and highlight important considerations for candidates and recipients of liver transplants.
Recent Findings
Ashwagandha, kava kava, green tea extract, skullcap, turmeric, and valerian have known idiosyncratic hepatotoxic potential and may complicate the liver transplantation course. Multiple supplements reportedly carry a lower risk of hepatotoxicity, though evidence for widespread use in those at risk for or with hepatic impairment is limited.
Summary
Psychiatrists caring for candidates and recipients of liver transplants must recognize that patients may find supplements helpful in alleviating psychiatric symptoms, despite an overall limited evidence base. Evaluating benefit versus risk ratios and reviewing drug-drug interactions is essential to promote transplant candidacy and mitigate the possibility of native or graft liver dysfunction.
... alcohol). It contains a large amount of interesting data, such as the possibility that turmeric in combination with tacrolimus may lead to increased edema and elevated creatinine levels [43]. Regarding food combinationdrug interactions, there are literature reports that since 1 January 2010, approximately 40% (67 out of 157 identified products) of the drugs approved by the EMA and FDA have exhibited significant food effects or require the drug to be taken with or without food [44]. ...
Diet–drug interactions (DDIs) are pivotal in drug discovery and pharmacovigilance. DDIs can modify the systemic bioavailability/pharmacokinetics of drugs, posing a threat to public health and patient safety. Therefore, it is crucial to establish a platform to reveal the correlation between diets and drugs. Accordingly, we have established a publicly accessible online platform, known as Diet-Drug Interactions Database (DDID, https://bddg.hznu.edu.cn/ddid/), to systematically detail the correlation and corresponding mechanisms of DDIs. The platform comprises 1338 foods/herbs, encompassing flora and fauna, alongside 1516 widely used drugs and 23 950 interaction records. All interactions are meticulously scrutinized and segmented into five categories, thereby resulting in evaluations (positive, negative, no effect, harmful and possible). Besides, cross-linkages between foods/herbs, drugs and other databases are furnished. In conclusion, DDID is a useful resource for comprehending the correlation between foods, herbs and drugs and holds a promise to enhance drug utilization and research on drug combinations.
... Turmeric increases the level of tacrolimus owing to cytochrome P450-3A4 (CYP3A4) inhibition [26,27]. Several cases reporting this interaction have been published [28][29][30]. People taking tacrolimus are advised to avoid large doses of turmeric. ...
Numerous investigations on herbal medicine that have been undertaken in the past several years demonstrate the general acceptance of its safety. The Saudi Food and Drug Authority (SFDA) established the Herb–Drug Interaction (HDI) project to detect and assess potential HDIs to ensure safety. The aim is to detect safety signals and assess them based on available evidence.
First, SFDA-registered herbal products (n = 30) were selected and prioritized based on commonly used herbs. Second, reported potential HDIs were retrieved from the World Health Organization global database of individual case safety reports (VigiBase), AdisInsight®, and the Natural Medicines database. We excluded drugs non-registered by SFDA and labeled interactions in the product information of SFDA, the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA). Finally, a comprehensive evaluation of potential HDIs was carried out using several evidence sources: literature, global cases, local cases, and other relevant documents. The Drug Interaction Probability Scale (DIPS) scale was used to assess the probability of a causal relationship between the interacting herb and drug and the event.
The search yielded 566 potential signals, and 41 had published evidence and were referred for assessment. The assessment results using DIPS were: 22 possible (53.6 %), 7 probable (17%), and 12 doubtful (29.2%) interactions. The recommendation was to include probable HDIs in the product information, including turmeric–tacrolimus, etoposide–Echinacea, Ginkgo biloba–ibuprofen, green tea–warfarin, and licorice–thiazides interactions.
The HDI project assessed the screening and identification of potential HDIs. The action plan of this project can be used in post-marketing activities to identify potential drug interactions.
... Turmeric has been shown to possess numerous medicinal values such as antioxidant, anti-inflammatory, nephronprotective, anti-diabetic, anti-lipedema, and anti-ulcerative properties [10]. However, scientific reports are revealing recently that consumption of turmeric at large dose can result into alteration of liver enzymes, blood thinning, ulceration and change in kidney function [11]. Therefore, this study was carried out to determine adverse effects associated with excess in-take of Curcuma longa in diet by evaluating serum and tissues total protein concentration and KIM-1. ...
... Frequency of CYP3A5 expression is distinct amongst ethnic groups, and genotype-guided dosing may assist TAC dose optimization in cardiac transplant recipients, particularly in the early post-operative period. [309][310][311][312][313] Drug Interactions: Many of the immunosuppressive agents, particularly the CNIs and mTOR inhibitors, undergo metabolism by CYP450 and p-glycoprotein, and there exists a high potential for drug interactions and changes in immunosuppressant levels which may lead to toxicity through excessive exposure, or potential graft rejection with sub-therapeutic levels. It is important to ensure that if an interacting agent (Table 5) is added or withdrawn to existing therapy, close monitoring of immunosuppressant drug levels and dose adjustments are made to avoid any adverse outcomes. ...
... In 2017, a case report outlined one of the first clinical cases of turmeric interacting with conventional medicines, in this case tacrolimus, resulting in acute calcineurin inhibitor nephrotoxicity [95] . Tacrolimus is metabolised by cytochrome P450 (CYP) 3A enzymes, and in previous studies, turmeric has been shown to inhibit CYP3A producing a similar degree of inhibition to grapefruit juice [ 96 , 97 ]. ...
Herbal traditional Chinese medicines (TCMs) are an increasingly popular alternative therapy globally. Due to the complex chemical composition of herbal products, and with research showing that consumers from Western countries are more likely to take multiple herbal products at one time, the lack of understanding of the potential side effects of herbal TCM may pose a significant risk to health and wellbeing. This may be particularly so now that herbal preparations are being promoted for the prevention and treatment of COVID-19 symptoms, often in association with Western medicines such as paracetamol. Of interest are the potential adverse effects of herbal TCMs on the kidney. Many factors can lead to the development of renal injury including intrinsic toxicity, plant misidentification, adulteration, contamination, and of increasing importance, interactions with conventional drugs and other herbs. This review evaluates and summarizes some of the key aspects of TCM-induced nephrotoxicity and the current scope of herb-drug and herb-herb interaction that may cause adverse effects.
... However, curcumin has been shown to significantly inhibit the activity of CYP3A4, which may alter metabolism of immunosuppressive medication [82]. In fact, there has been a reported case on supratherapeutic tacrolimus level in a liver transplant recipient who consumed a high dose of curcumin through ingestion of turmeric with food [83]. However, the patient in this case reported to have taken 15 spoonsful of turmeric/day, significantly above the recommended 1 2 to 1 teaspoon/day (2.5-5 g/day). ...
Hyperglycemia after kidney transplantation is common in both diabetic and non-diabetic patients. Both pretransplant and post-transplant diabetes mellitus are associated with increased kidney allograft failure and mortality. Glucose management may be challenging for kidney transplant recipients. The pathophysiology and pattern of hyperglycemia in patients following kidney transplantation is different from those with type 2 diabetes mellitus. In patients with pre-existing and post-transplant diabetes mellitus, there is limited data on the management of hyperglycemia after kidney transplantation. The following article discusses the nomenclature and diagnosis of pre- and post-transplant diabetes mellitus, the impact of transplant-related hyperglycemia on patient and kidney allograft outcomes, risk factors and potential pathogenic mechanisms of hyperglycemia after kidney transplantation, glucose management before and after transplantation, and modalities for prevention of post-transplant diabetes mellitus.
... longa L.), болдо (Peumus boldus Molina) и настой ромашки лекарственной (Matricaria chamomilla L., сем. Asteraceae) [59][60][61]. Индуцированное циклоспорином поражение почек было описано у реципиентов органов и у пациентов с аутоиммунными заболеваниями. Циклоспорин вступал в реакцию с белками семейства иммунофилинов, ингибируя опосредованную кальциневрином активацию Т-лимфоцитов. ...
Herbal medicines make up a large part of all medicinal products in the Russian market. Complex combinations of biologically active substances that are used as components in herbal medicines not only determine their therapeutic efficacy, but can also cause adverse reactions. The aim of this review was to analyse data on adverse effects of herbal medicines, and reasons and mechanisms behind their development. Special attention should be given to hepatotoxic and nephrotoxic effects of biologically active substances that are used as components in herbal medicines, because liver and kidney failure may lead to life-threatening conditions. The paper addresses hepatic adverse effects, including sinusoidal obstruction syndrome, caused by toxic biologically active substances of the pyrrolizidine alkaloids group. The paper summarises data on herbal medicines and toxic biologically active substances causing acute kidney injury and chronic kidney disease. It analyses potential clinically significant interactions that may occur during co-use of herbal and other types of medicines due to their pharmacokinetic and pharmacodynamic interactions. Further research involving collection, systematisation, and analysis of adverse effects of herbal medicines used alone or in combination with other medicinal products is needed to improve the safety of pharmacotherapy.
... The potential for drug interactions has been recognized, with dose-dependent inhibition of cytochrome p450 subtypes CYP3A4 and CYP1A2 in the liver [23] and intestines [24] identified. Accordingly, the addition of curcumin to medications metabolized by CYP3A4 can lead to an increase in plasma levels, with curcumin associated with acute calcineurin inhibitor nephrotoxicity due to CYP3A4 inhibition [25]. ...
Turmeric is a commonly used oral herbal supplement with purported anti-inflammatory and antineoplastic properties. It is promoted as safe, with limited reports of severe adverse effects directly related to oral turmeric thus far in the literature. Herein we report two cases of turmeric supplement induced severe hepatitis. These cases highlight the need for physicians to be aware of patients taking this common supplement and the potential risks that exist.
... [5][6][7] Moreover, multiple reports exist of adverse events and altered treatment effects for various medications that have been taken in conjunction with ginkgo biloba extract, cranberry juice extracts, turmeric and quercetin. [8][9][10][11] For this reason, risk assessments of dietary supplement-drug interactions are essential. ...
Thylakoid-rich spinach extract is being used as dietary weight-loss supplements in Japan. A recent rat study has suggested that intake of thylakoid-rich spinach extract with dietary oil inhibits dietary fat absorption via binding to bile acids, which promotes excretion of bile acids in feces. While, we confirmed that a serving size of thylakoid-rich spinach extract contains a large amount of calcium (130 mg/5 g). Therefore, using rats, we evaluated whether one-time ingestion of thylakoid-rich spinach extract affects the gastrointestinal absorption of water-insoluble drugs, such as griseofulvin (GF) and indomethacin (IM), or ciprofloxacin (CPFX) that chelate with polyvalent metal cations. Pretreatment of the rats with thylakoid-rich spinach extract (100 or 300 mg/kg) for 15 min prior to oral administration of GF (50 mg/kg) or IM (10 mg/kg) did not significantly alter the pharmacokinetic properties of either drug. Meanwhile, co-administration of thylakoid-rich spinach extract (500 mg/kg) and CPFX (20 mg/kg) significantly reduced the peak plasma concentration and the area under the plasma concentration-time curve of CPFX to 25 and 40%, respectively in rats. In vitro studies demonstrated that when a mixture of thylakoid-rich spinach extract and CPFX was centrifuged, there was a significant reduction in the supernatant concentration of CPFX relative to the control. When the experiment was repeated in the presence of ethylenediaminetetraacetic acid, the concentration of CPFX was unchanged. These results suggest that the intake of thylakoid-rich spinach extract may reduce the absorption of drugs that form a chelate with polyvalent metal cations, such as CPFX.
Graphical Abstract Fullsize Image
... The AA nephropathy is described by broad renal interstitial fibrosis and tubular decay, which for the most part diminishes in force from the external to the inward cortex (Tanaka et al., 2000). Nayeri et al. (2017) reported in a case of a 54-year-old man who expended extensive doses of turmeric, or around 15 + spoonfuls consistently for 10 days allegedly had renal issues. He had a kidney transplant and was on tacrolimus to stop rejection. ...
Phytochemicals are bioactive plant compounds that can be used as antimicrobial, antibacterial, anticancer agents and are reported to prevent cancer, cardiovascular and inflammatory diseases. Herbs and spices are rich in phytochemicals and can be consumed or used traditionally for medical or dietary purposes since the ancient times. However, there may be serious health risks for some population groups such as pregnant women and infants in the case of their unconscious and uncontrolled consumption. Several in vivo and in vitro studies related with the toxicological effects of phytochemicals in herbs and spices created awareness among consumers. These studies indicate the dose dependent effects of phytochemicals in herbs and spices showing toxicological effects at high doses whereas can also be health promoting at lower doses. In this review, two faces of herbs and spices were evaluated in every aspect.
The well-established calcineurin inhibitor, tacrolimus, as an immunosuppressive agent, is widely prescribed after organ transplantation. Cytochrome P450 (CYP 450) isoforms are responsible for the metabolism of many features associated with food parameters like phytochemicals, juices, and fruits. This review article summarizes the findings of previous studies to help predict the efficacy or side effects of tacrolimus in the presence of food variables. From the commencement of databases associated with the topic of interest to 26 October 2024, all relevant articles were searched through PubMed, Scopus, and Web of Science. The suggested therapeutic range for tacrolimus trough concentration (C) was reported as 5-15 ng/ml blood. Tacrolimus interaction with food variables could significantly change C after organ transplantation. For example, grapefruit juice could increase tacrolimus C due to CYP enzyme inhibition. Toxicity such as nephrotoxicity could result from turmeric and other herbal or food products. By inhibiting tacrolimus-metabolizing enzymes and transporters, a high intake of vegetables could increase the risk of adverse effects. Secondary metabolites of vegetables could lead to toxicity in patients with tacrolimus. Furthermore, grapefruit juice, citrus fruits, turmeric, and pomegranate juice could change clinical pharmacokinetics parameters such as Tmax, Cmax, AUC, and C of tacrolimus after organ transplantation. Bioavailability of tacrolimus might be decreased by induction of the CYP450 system and P-gp efflux pump due to cranberry, rooibos tea, and boldo. Increased inhibitory effect on CYP450 system and/or P-gp efflux pump by grapefruit juice, schisandra, berberine, turmeric, pomegranate juice, pomelo, and ginger could increase bioavailability of tacrolimus. A vigilant immunosuppressive strategy accompanied by scheduled therapeutic drug monitoring is recommended before and after transplant surgery.
Background
The use of herbal medicines is on the rise throughout the world due to their perceived safety profile. However, incidences of herb-drug, herb-herb and herb-food interactions considering safety aspects have opened new arenas for discussion.
Objective
The current study aims to provide comprehensive insights into the various types of herb interactions, the mechanisms involved, their assessment, and historical developments, keeping herbal safety at the central point of discussion.
Methods
The authors undertook a focused/targeted literature review and collected data from various databases, including Science Direct, Wiley Online Library, Springer, PubMed, and Google Scholar. Conventional literature on herbal remedies, such as those by the WHO and other international or national organizations.
Results
The article considered reviewing the regulations, interaction mechanisms, and detection of herb-herb, herb-drug and herb-food interactions in commonly used yet vital plants, including Glycyrrhiza glabra, Mentha piperita, Aloe barbadensis, Zingiber officinale, Gingko biloba, Withania somnifera, etc. The study found that healthcare professionals worry about patients not informing them about their herbal prescriptions (primarily used with conventional treatment), which can cause herb-drug/herb-food/herb-herb interactions. These interactions were caused by altered pharmacodynamic and pharmacokinetic processes, which might be explained using in-vivo, in-vitro, in-silico, pharmacogenomics, and pharmacogenetics. Nutrivigilance may be the greatest method to monitor herb-food interactions, but its adoption is limited worldwide.
Conclusion
This article can serve as a lead for clinicians, guiding them regarding herb-drug, herb-food, and herb-herb interactions induced by commonly consumed plant species. Patients may also be counseled to avoid conventional drugs, botanicals, and foods with a restricted therapeutic window.
Warfarin is a popular anticoagulant with high global demand. However, studies have underlined serious safety issues when warfarin is consumed concomitantly with herbs or its formulations. This review aimed to highlight the mechanisms behind herb-warfarin interactions while laying special emphasis on its PKPD interactions and evidence on Herb-Warfarin Interaction (HWI) with regards to three different scenarios, such as when warfarin is consumed with herbs taken as foods or prescribed as medicine, or when used in special situations. A targeted literature methodology involving different scientific databases was adopted for acquiring information on the subject of HWIs. Results of the present study revealed some of the fatal consequences of HWI, including post-operative bleeding, thrombosis, subarachnoid hemorrhage, and subdural hematomas occurring as a result of interactions between warfarin and herbs or commonly associated food products from Hypericum perforatum, Zingiber officinale, Vaccinium oxycoccos, Citrus paradisi, and Punica granatum. In terms of PK-PD parameters, herbs, such as Coptis chinensis Franch. and Phellodendron amurense Rupr., were found to compete with warfarin for binding with plasma proteins, leading to an increase in free warfarin levels in the bloodstream, resulting in its augmented antithrombic effect. Besides, HWIs were also found to decrease International Normalised Ratio (INR) levels following the consumption of Persea americana or avocado. Therefore, there is an urgent need for an up-to-date interaction database to educate patients and healthcare providers on these interactions, besides promoting the adoption of novel technologies, such as natural language processing, by healthcare professionals to guide them in making informed decisions to avoid HWIs.
Tacrolimus is a widely used immunosuppressant for the prevention of rejection after transplantation. In vitro studies suggest that interactions exist between spices and tacrolimus. We present the case of a renal transplant patient aged around 70 years who was treated with prednisone, mycophenolate-mofetil and tacrolimus. The patient had a pre-transplant dietary habit of consuming foods spiced with turmeric, curry and ginger. The following protocol was implemented in parallel with close monitoring of plasma tacrolimus concentrations: administration of 10 g/day of turmeric for 4 days, then 10 g/day of curry for 4 days and then 10 g/day of ginger for 4 days. No change in tacrolimus plasma concentrations during and after the implementation of the protocol was observed. The impact of turmeric, curry and ginger on plasma tacrolimus concentrations seems negligible in vivo although further studies are needed. A shared decision to test the impact of spice consumption in a patient with dietary habits involving these spices seems reasonable.
Ethnopharmacology relevance:
Picrorhiza scrophulariiflora Pennell, a well-known Chinese herb, has been traditionally utilized as an antioxidant and anti-inflammatory agent. One of its main bioactive components is Picroside II, a glycoside derivative. However, there is limited information on the effects of Picroside II on the activity of cytochrome P450 (CYP) enzymes nor on potential herb-drug interactions are rarely studied.
Aim of the study:
The purpose of the study was to investigate the effects of Picroside II on the activity of cytochrome P450 enzymes in vitro and in vivo and its potential herb-drug interactions.
Materials and methods:
Specific probe substrates were employed to assess the effect of Picroside II on the activity of P450 enzymes. The inhibitory effects of Picroside II on CYP enzymes were assayed both in human (i.e., 1A, 2C9, 2C19, 2D6, 2E1, and 3A) and rat (i.e., 1A, 2C6/11, 2D1, 2E1, and 3A) liver microsomes in vitro. The inductive effects were investigated in rats following oral gavage of 2.5 mg/kg and 10 mg/kg Picroside II. A specific Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) method was developed to determine the formation of specific metabolites.
Results:
Enzyme inhibition results showed that Picroside II (0.5-200 μM) had no evident inhibitory effects on rat and human liver microsomes in vitro. Interestingly, the administration of multiple doses of 10 mg/kg Picroside II inhibited the activity of CYP2C6/11 by reducing the rate of formation of 4-hydroxydiclofenac and 4-hydroxymephenytoin, while Picroside II at 2.5 mg/kg increased the activity of CYP3A by promoting the formation of 1-hydroxymidazolam and 6-hydroxychlorzoxazone in rats. In addition, there were negligible effects on CYP1A, CYP2D1, and CYP2E1 in rats.
Conclusions:
The results indicated that Picroside II modulated the activities of CYP enzymes and was involved in CYP2C and CYP3A medicated herb-drug interactions. Therefore, careful monitoring is necessary when Picroside II is used in combination with related conventional drugs.
Herb medicine has a long history of application and is still used worldwide. With the development of complementary and alternative medicine, the interaction between herb and drugs has attracted more and more attention. Herb-drug interactions (HDI) could cause decreased efficiency, increased toxicity, and affect the drug absorption and disposition processes due to the interference of their pharmacological or pharmacokinetic effects. Hence, the mechanisms and results of herb-pharmacokinetic interactions should be comprehensively summarized. Here, we have summarized the mechanisms of HDI and pharmacokinetic interactions in the last ten years based on searching on PubMed, Science Direct, and Web of Science with different keywords. Besides, the pharmacokinetic interactions were related to nine commonly used herbs and drugs, including Ginseng, Salvia miltiorrhiza, Ginkgo biloba, Garlic, Coptis chinensis, St. John's wort, Ginger, Licorice, Silythistle and Fructus Schisandrae. This review provides an overview of HDI to provide a reference for the rational and safe clinical use of herbs and drugs.
Herbal food supplements are commonly used and can be an important part of patient self-care. Like all other bio-active and therapeutic products, they have a benefit/risk balance. These products are not without adverse effects and potentially interact with other therapies. Educating patients and providing information for health professionals about the risk of herb–drug interactions is key. One of the purposes of the biomedical literature is to inform prescribers. Scientific literature accessible on databases such as PubMed is dense and careful reading is time consuming. We propose a reading aid tool named “HDI highlighter” to help readers to find key information in clinical studies and case reports describing herb–drug interactions. It uses natural language processing algorithms (artificial intelligence) with a pharmaceutical focus. Semantic relation extraction for herb–drug interactions from the biomedical literature are overexpressed using keywords. We have tested it to review 120 published articles over the last 10 years. In these articles, we have shown that case reports often involved long-term or semi-long-term treatments such as cancer or human immunodeficiency virus therapies, antiepileptic drugs, or central nervous system drugs. Similarly, these classes of drugs are more extensively targeted by clinical studies. Herb–drug interactions described in case reports are identified in medicinal, recreational, and alimentary uses. They also usually lack a rigorous description of the herb(s) involved. Typically, clinical studies provide a complete description of protocols and dosages, with a few exceptions explained by patients’ needs. Clinical studies on herbs are nevertheless conducted on a limited number of patients. All these limitations make the interpretation of herb–drug interactions complicated, but the HDI highlighter provides a quick overview of the herb–drug interaction literature.
The calcineurin inhibitor tacrolimus (TAC) shows inter-and intra-individual variability in blood levels and has a narrow therapeutic index. To reduce the chance of fluctuations in immunosuppressive activity and potential drug interactions, it is critical to keep track of drug concentrations. Cytochrome-P450 (CYP) isoenzymes CYP3A4 and CYP3A5, as well P-glycoprotein (P-gp) are involved in TAC bioavailability. TAC's interactions with herbal extracts are reviewed here, because with more people using TAC, it is becoming crucial to know which extracts, which are often part of self-medication, can alter TAC blood concentrations. TAC bioavailability was decreased when co-administered with St John's wort (SJW), cranberry, rooibos tea, and boldo in human models by induction of the CYP450 system and/or P-gp efflux pump, meanwhile, the TAC bioavailability was increased when co-administered with grapefruit juice (GFJ), schisandra, berberine, turmeric, pomegranate juice, pomelo, and ginger in human and or animal models by inhibition effect on CYP450 system and/or P-gp efflux pump. Thus, physicians and pharmacists should thoroughly educate their patients regarding the use of supplemental herbs before administering TAC. Furthermore, patients who are already undergoing TAC treatment should be informed about the possibility of dangerous interactions between herbal remedies and TAC.
This review examines three bodies of literature related to herb–drug interactions: case reports, clinical studies, evaluations found in six drug interaction checking resources. The aim of the study is to examine the congruity of resources and to assess the degree to which case reports signal for further study. A qualitative review of case reports seeks to determine needs and perspectives of case report authors. Methods: Systematic search of Medline identified clinical studies and case reports of interacting herb–drug combinations. Interacting herb–drug pairs were searched in six drug interaction resources. Case reports were analyzed qualitatively for completeness and to identify underlying themes. Results: Ninety-nine case-report documents detailed 107 cases. Sixty-five clinical studies evaluated 93 mechanisms of interaction relevant to herbs reported in case studies, involving 30 different herbal products; 52.7% of these investigations offered evidence supporting reported reactions. Cohen’s kappa found no agreement between any interaction checker and case report corpus. Case reports often lacked full information. Need for further information, attitudes about herbs and herb use, and strategies to reduce risk from interaction were three primary themes in the case report corpus. Conclusions: Reliable herb–drug information is needed, including open and respectful discussion with patients.
The clinical application of herbal medicines is increasing, but there is still a lack of comprehensive safety data and in-depth research into mechanisms of action.The composition of herbal medicines is complex, with each herb containing a variety of chemical components. Each of these components may affect the activity of metabolizing enzymes, which may lead to herb-drug interactions. It has been reported that the combined use of herbs and drugs can produce some unexpected interactions. Therefore, we have reviewed the progress of research on safety issues caused by the effects of herbs on metabolizing enzymes with reference to six categories of drugs, including antithrombotic drugs, non-steroidal anti-inflammatory drugs, antidiabetic drugs, statins lipid-lowering drugs, immuno suppressants and antineo plastic drugs. Under-standing the effects of herbs on the activity of metabolizing enzymes can avoid the toxicity and adverse drug reactions resulting from the co-administration of herbs and drugs, and help doctors to reduce the risk of prescription incompatibility.
RESUMEN Introducción: En la actualidad se presenta un aumento en el número de personas que requieren un trasplante de órganos y para evitar el rechazo del órgano trasplantado, se requiere la administración de medicamentos como tacrolimus, para evitar el rechazo del trasplante. Objetivo: Caracterizar los eventos adversos asociados al uso del tacrolimus, obtenidos a través de farmacovigilancia pasiva por el Programa Distrital de Farmacovigilancia D.C. de Bogotá. Métodos: Se realiza un análisis con algoritmo OMS para reacciones adversas, del Centro de Información en Medicamentos de la Universidad Nacional de Colombia para fallo terapéutico y de acuerdo al Tercer Consenso de Granada para problemas relacionados con tacrolimus. Resultados: Fueron reportados 50 eventos, y todos corresponden a reacciones adversas a tacrolimus. El 78 % de los eventos adversos con tacrolimus ocurrió en hombres. El 59 % de los eventos asociados al uso de tacrolimus corresponden a reacciones graves. El 54 % de los reportes de eventos adversos a tacrolimus corresponden al año 2015. En el 60 % (30) de los reportes existen otras causas asociadas al evento adverso, pero no se descarta la asociación del evento con el uso del medicamento. Se destaca principalmente poliomielitis, nefrotoxicidad, infecciones urinarias, neumonía y arritmias. En tres reportes hay potenciales interacciones con claritromicina, omeprazol, lovastatina, micofenolato de mofetilo y prednisolona. El trasplante renal fue la principal indicación en el 72 % de los reportes. Conclusiones: En condiciones reales de uso se presentan reacciones adversas a tacrolimus, que a través de un mayor conocimiento de las comorbilidades o factores de riesgo del paciente son potencialmente evitables. Palabras clave: tacrolimus; farmacoepidemiología; utilización de medicamentos. ABSTRACT Introduction: Currently, there is an increase in the number of people that require an organ transplant, and to avoid rejection of the transplanted organ patients require the administration of drugs such as tacrolimus. However, in the case of these medicines it is necessary to extend the safety profile through the pharmacovigilance programs. Objective: To analyze and characterize the adverse events associated with the use of tacrolimus obtained through passive pharmacovigilance by the Pharmacovigilance´s District Program, Bogotá D.C from 2012 to 2015. Methods: An analysis with the WHO's algorithm for adverse reactions, a test of the Center of Information in Drugs of the National University of Colombia (CIMUNC by its acronym in Spanish) for therapeutic failure and the Third Consensus of Granada for problems related to tacrolimus were performed. Results: 50 events were reported, of which all correspond to adverse reactions to tacrolimus. 78 % of the adverse events with tacrolimus occurred in the male gender. 59 % of the events associated with the use of tacrolimus correspond to serious reactions, of which 24 % required hospitalization. 54 % of the reports of adverse events related with tacrolimus correspond to the year 2015. In 60 % (30) of the reports there are other causes associated with the adverse event, but the association of the event with the use of the medication is not ruled out. Adverse reactions include polio, nephrotoxicity, urinary tract infections, pneumonia
The use of dietary supplements (DS), herbal and other, continues to increase globally. With this increased use and growing awareness of the potential for harm from DS, the need for pharmacovigilance is more obvious. New reports of harm from homeopathy products are found in the lay press and acted upon by governmental agencies. The systems that track adverse events due to these products progress by use of databases, such as the FDA's CAERS and health tracking systems, such as DILINS and the public health systems of many countries. This review of adverse events by organ system shows a varied array of disorders caused by DS and as potential and actual drug–nutrient interactions. Other CAM, including acupuncture and mind–body therapies, are shown to not be innocuous.
Many older people who have emigrated from Vietnam to the United States continue to use the traditional medicines that they used in their country of origin. Clinicians trained in the West may not be familiar with these products. We reviewed 6 Asian traditional medicines that are popular among older Vietnamese people living in the United States. Each medicine has significant side effects that can lead to complications in patients undergoing surgery. Here, we present the case of a patient who used Cordyceps sinensis daily as a tonic and experienced prolonged bleeding after dental surgery.
Aim:
The aim of this review was to assess the severity of adverse drug reactions (ADRs) due to herb-drug interactions in patients taking herbs and prescribed medications based on published evidence.
Method:
Electronic databases of PubMed, the Cochrane Library, Medline and Scopus were searched for randomized or non-randomized clinical studies, case-control and case reports of herb-drug interactions (HDI). The data was extracted and the causal relationship of ADRs as consequences of HDI assessed using Horn's drug interaction probability scale (DIPS) or Roussel Uclaf Causality Assessment Method (RUCAM) scoring systems. The mechanism of interaction was ascertained using Stockley's herbal medicine interaction companion.
Results:
Forty-nine case reports and two observational studies with 15 cases of ADRs were recorded. The majority of the patients were diagnosed with cardiovascular diseases (30.60%), cancer (22.45%) and renal transplants (16.32%) receiving mostly warfarin, alkylating agents and cyclosporine, respectively.
Conclusion:
HDI occurred in patients resulting in clinical ADRs with different severity. Patients may poorly respond to therapeutic agents or develop toxicity due to severe HDI which in either scenario may increase the cost of treatment and /or lead to or prolong patient hospitalisation. It is warranted to increase patient awareness of the potential interaction between herbs and prescribed medicines and their consequences to curb HDI as a potential health problem.
The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.
Tacrolimus (FK-506) is an immunosuppressant agent that acts by a variety of different mechanisms which include inhibition of calcineurin. It is used as a therapeutic alternative to cyclosporin, and therefore represents a cornerstone of immunosuppressive therapy in organ transplant recipients. Tacrolimus is now well established for primary immunosuppression in liver and kidney transplantation, and experience with its use in other types of solid organ transplantation, including heart, lung, pancreas and intestinal, as well as its use for the prevention of graft-versus-host disease in allogeneic bone marrow transplantation (BMT), is rapidly accumulating.
Large randomised nonblind multicentre studies conducted in the US and Europe in both liver and kidney transplantation showed similar patient and graft survival rates between treatment groups (although rates were numerically higher with tacrolimus-versus cyclosporin-based immunosuppression in adults with liver transplants), and a consistent statistically significant advantage for tacrolimus with respect to acute rejection rate. Chronic rejection rates were also significantly lower with tacrolimus in a large randomised liver transplantation trial, and a trend towards a lower rate of chronic rejection was noted with tacrolimus in a large multicentre renal transplantation study.
In general, a similar trend in overall efficacy has been demonstrated in a number of additional clinical trials comparing tacrolimus-with cyclosporin-based immunosuppression in various types of transplantation. One notable exception is in BMT, where a large randomised trial showed significantly better 2-year patient survival with cyclosporin over tacrolimus, which was primarily attributed to patients with advanced haematological malignancies at the time of (matched sibling donor) BMT. These survival results in BMT require further elucidation. Tacrolimus has also demonstrated efficacy in various types of transplantation as rescue therapy in patients who experience persistent acute rejection (or significant adverse effects) with cyclosporin-based therapy, whereas cyclosporin has not demonstrated a similar capacity to reverse refractory acute rejection. A corticosteroid-sparing effect has been demonstrated in several studies with tacrolimus, which may be a particularly useful consideration in children receiving transplants.
The differences in the tolerability profiles of tacrolimus and cyclosporin may well be an influential factor in selecting the optimal treatment for patients undergoing organ transplantation. Although both drugs have a similar degree of nephrotoxicity, cyclosporin has a higher incidence of significant hypertension, hypercholesterolaemia, hirsutism and gingival hyperplasia, while tacrolimus has a higher incidence of diabetes mellitus, some types of neurotoxicity (e.g. tremor, paraesthesia), diarrhoea and alopecia.
Conclusion: Tacrolimus is an important therapeutic option for the optimal individualisation of immunosuppressive therapy in transplant recipients.
Pharmacodynamic Properties
Tacrolimus (FK-506) is a macrolide immunosuppressant that acts by a variety of different mechanisms which include inhibition of calcineurin. The drug inhibits T lymphocyte activation and transcription of cytokine genes including that for interleukin-2. Tacrolimus inhibits cell-mediated and, to a lesser extent, humoral immune responses. Cytokines produced by T helper (Th)1 cells are preferentially suppressed over those produced by Th2 cells.
The mechanism of action of tacrolimus is largely similar to that of cyclosporin, but tacrolimus is 10 to 100 times more potent. The drugs both inhibit calcineurin but do so via formation of complexes with different immunophilins: tacrolimus binds to FK-506 binding protein 12, whereas cyclosporin binds to cyclophilin A. The drugs appear to differ in their effects on patterns of Th2 cell cytokine expression and possibly some aspects of humoral immunity. Furthermore, lymphocyte sensitivity to the drugs may differ between patients.
In animal models, tacrolimus had an organ-specific effect in stimulating hepatic regeneration after partial hepatectomy, and attenuated hepatic ischaemic or reperfusion injury. Tacrolimus does not appear to cause postoperative cholestasis in liver transplant recipients, and postoperative disturbances in biliary secretion and flow rates may recover more rapidly with tacrolimus than cyclosporin.
Like cyclosporin, tacrolimus has nephrotoxic effects that appear to be mechanistically related to its immunosuppressive activity, possibly involving inhibition of calcineurin. Tacrolimus suppresses insulin production at the trans-criptional level and appears to be more diabetogenic than cyclosporin in some patients. In patients with liver transplants, tacrolimus reduced β cell secretory reserve, and was associated with significant insulin resistance and impaired β cell-α cell axis.
Further clarification is required of the comparative effects of tacrolimus and cyclosporin on factors involved in cardiac transplant-associated coronary artery disease. Although tacrolimus has been associated with a lower incidence of positivity for anti-endothelial cell antibodies than cyclosporin, a higher incidence of pathological microvascular endothelial dysfunction has also been reported. Tacrolimus may have an in vitro antithrombotic effect. Findings have been conflicting regarding the comparative effect of tacrolimus and cyclosporin on endothelium-independent microcirculatory responses 1 year after cardiac transplantation. Tacrolimus and cyclosporin appear to have similar effects on most aspects of cardiac function in renal or liver transplant recipients.
Pharmacokinetic Propertie
Like cyclosporin, the pharmacokinetic properties of tacrolimus can vary widely between individuals and dosage regimens are titrated according to whole-blood trough drug concentrations. Oral bioavailability of tacrolimus is about 20 to 25%, and food appears to have a significant effect in reducing the rate and extent of absorption. The drug binds extensively to erythrocytes, and whole-blood concentrations of tacrolimus are approximately 15 to 35 times those measured in plasma. Tacrolimus is almost completely metabolised prior to elimination. Metabolism is via 3A4 isoenzymes of the cytochrome P450 (CYP) system, primarily in the liver but also in the intestinal mucosa, and a number of metabolites are formed. At least 1 metabolite appears to be active, although the immunosuppressive activity of tacrolimus is primarily due to the parent drug. Elimination half-life of tacrolimus has been reported to be approximately 12 hours in liver transplant recipients and 19 hours in renal transplant recipients. Less than 1% of an intravenous dose of tacrolimus is eliminated unchanged in the urine. The main route of elimination for tacrolimus and its metabolites is via the biliary tract. Like cyclosporin, tacrolimus is subject to a number of pharmacokinetic (and pharmacodynamic) drug interactions of potential clinical significance, including those involving other drugs metabolised by the CYP enzyme system.
Therapeutic Efficacy
In most clinical trials, tacrolimus-based primary immunosuppression initially included concomitant administration of corticosteroids, typically with azathioprine or mycophenolate mofetil, and sometimes with adjunctive antilymphocyte antibody induction therapy. In general, rescue therapy with tacrolimus usually involved simple conversion from cyclosporin to tacrolimus without modification of concomitant drug therapy. Clinical trials comparing tacrolimus-with cyclo-sporin-based immunosuppression were conducted in a nonblind fashion, presumably because of the need to monitor whole-blood trough drug concentrations to optimise the clinical management of patients. In the following sections, cyclosporin refers to the standard formulation of the drug (the microemulsion formulation is specified when applicable).
Hepatic Transplantation
As primary immunosuppression in adults with hepatic transplantation, tacrolimus-based regimens achieved similar patient and graft survival rates to cyclosporin-based regimens, with a trend towards higher rates with tacrolimus, and significantly lower rates of acute rejection. This was demonstrated in 2 large multicentre randomised trials, one of which also showed significantly lower rates of chronic rejection at 1 and 3 years post-transplantation among patients receiving tacrolimus-based immunosuppression.
In general, similar overall efficacy trends were noted in more recent smaller randomised studies comparing tacrolimus with the cyclosporin microemulsion formulation. Results of these studies showed patient and graft survival rates of approximately 75 to 100% and 70 to 95%, respectively, after 6 to 30 months of tacrolimus-based therapy; acute rejection rates varied widely between studies. Long term survival data from a large cohort of 1000 patients treated with tacrolimus-based immunosuppression after liver transplantation indicate 6-year patient and graft survival rates of 68 and 63%, respectively. Several studies demonstrated that corticosteroid therapy could be successfully withdrawn in approximately 70 to 90% of liver transplant recipients treated with tacrolimus-based immunosuppressive therapy.
Tacrolimus is also effective as rescue therapy in adult patients with persistent acute or chronic rejection or drug-related toxicity with cyclosporin-based primary immunosuppression after hepatic transplantation. This has been demonstrated in a number of noncomparative studies, the largest involving a group of 475 patients with 2-year patient and graft survival rates of 80 and 73%, respectively, after conversion from cyclosporin to tacrolimus because of acute or chronic rejection.
In general, results of studies with tacrolimus-based primary immunosuppressive and rescue therapy for paediatric liver transplantation have been very similar to those of studies in adult patients. Results of the only prospective randomised comparison between tacrolimus (n = 30; mean age 3.5 years) and cyclosporin (n = 21; mean age 3.2 years) as primary immunosuppression showed similar 1-year patient (80 vs 81%) and graft (70 vs 71%) survival rates, and a trend favouring tacrolimus for acute rejection rate (52 vs 79%). Importantly, some studies demonstrated that corticosteroid therapy can be successfully discontinued in approximately 70 to 85% of children receiving tacrolimus as primary immunosuppressive or rescue therapy.
Renal Transplantation
Tacrolimus-based regimens achieved similar patient and graft survival rates and lower rates of acute rejection compared with cyclosporin-based regimens when used as primary immunosuppression in adults with renal transplantation. This was demonstrated in 2 large multicentre randomised trials; 1-year patient survival rates were ≈95% and corresponding graft survival rates were ≈85 to 90% for both treatment groups. A statistically significant advantage favouring tacrolimus for acute rejections rates was noted in both studies (26 vs 46% and 31 vs 46%; both p < 0.001). One of the multicentre studies (European data) showed a nonsignificant trend towards a lower rate of chronic rejection among tacrolimus recipients than cyclosporin recipients at 4 years post-transplantation (5.5 vs 11.3%). Long term (3-year) survival data from one of the trials (US data) showed similar rates of patient (≈90%) and graft (≈80%) survival for both treatment groups. In this study, approximately 25% of patients were African-American, and results in this high-risk subgroup mirrored those for all patients in each treatment group. Numerous noncomparative, retrospective or meta-analytical trials, as well as a few small-to moderate-sized randomised comparisons with cyclosporin microemulsion, have also been conducted with tacrolimus-based regimens for primary immunosuppression in adult renal transplant recipients, and results generally support those of the large multicentre studies.
Rescue therapy with tacrolimus, primarily in patients who developed acute rejection while receiving cyclosporin-based primary immunosuppression (n = 40 to 169), was associated with patient survival rates >90% and corresponding graft survival rates >70% after 1 to 3 years of follow-up after conversion. In general, results of studies with tacrolimus-based primary immunosuppressive and rescue therapy for paediatric renal transplantation have been very similar to those of studies in adult patients. In the largest study, 81 children (82 transplants) received tacrolimus-based therapy as primary immunosuppression. One-year patient and graft survival rates approached 100%, and 4-year rates were 94 and 84%, respectively. About two-thirds of patients were successfully withdrawn from corticosteroid therapy.
Heart Transplantation
In prospective studies comparing tacrolimus-with cyclosporin-based primary immunosuppressive regimens in heart transplant recipients, patient survival rates were similar between treatment groups and there was a consistent trend towards more favourable acute rejection rates with tacrolimus. One-and ≈2-year patient survival rates were ≈80 to 90% for both treatment groups, and a large non-randomised comparison also showed similar 5-year patient survival rates between tacrolimus and cyclosporin treatment groups (76 vs 71%). In a moderate-sized randomised study of 73 patients, the mean number of acute rejection episodes per patient was significantly lower among tacrolimus than cyclosporin recipients (1.33 vs 1.87; p < 0.01). A number of small studies (n < 20) of tacrolimus as rescue therapy in adults showed that at least 70% of patients had either no rejection episodes or only mild rejection after conversion from cyclosporin to tacrolimus (follow-up periods were usually at least 6 months).
Tacrolimus has had limited use in paediatric heart transplantation. Tacrolimus-based primary immunosuppression was associated with good patient survival rates in a group of 26 children (≈80% at 1 and 3 years post-transplantation). In addition, rates of moderate to severe acute rejection were lower and corticosteroid withdrawal rates were much higher than those in historical controls treated with cyclosporin-based therapy. The results of a nonrandomised study of 40 paediatric heart transplant recipients showed that the presence of 2 HLA-DR loci donor/ recipient mismatches increased the risk of high-grade rejection in children receiving cyclosporin-based therapy, whereas the risk of rejection was not increased in those receiving tacrolimus-based therapy. Tacrolimus-treated children with 2 HLA-DR mismatches had a significantly lower risk of severe rejection than cyclosporin-treated children with only 1 HLA-DR mismatch. In small studies (n < 25) of tacrolimus as rescue therapy, graft loss was not reported (follow-up periods up to 40 months) and corticosteroid dosages were reduced or discontinued in most children.
Lung Transplantation
Tacrolimus-and cyclosporin-based primary immunosuppressive regimens were associated with similar 1-(83 vs 71%) and 2-year (76 vs 66%) patient survival rates, as well as similar proportions of patients free from acute rejection (14 vs 11.5%), in a prospective randomised study of 133 lung transplant recipients. Results for all of these end-points tended to favour tacrolimus, and the trial showed a significantly lower incidence of obliterative bronchiolitis among tacrolimus than cyclosporin recipients (21.7 vs 38%; p < 0.05).
In general, the use of tacrolimus as rescue therapy in small numbers of patients with lung transplantation (n ≤15) was associated with a reduced incidence of acute rejection after conversion from cyclosporin, and at least two-thirds of patients remained alive during mean follow-up periods of approximately 6 to 18 months.
Pancreas or Kidney and Pancreas Transplantation
Numerous studies have been conducted demonstrating the efficacy of tacrolimus as primary immunosuppression after solitary pancreas transplantation or simultaneous pancreas and kidney transplantation (SPK); however, no large randomised trial has prospectively compared tacrolimus-with cyclosporin-based regimens in this clinical setting. Nevertheless, data from 2 large (n > 200) retrospective analyses indicate significantly better pancreas graft survival with tacrolimus-based therapy in patients with solitary pancreas or SPK transplantation, and patient and renal graft survival was better with tacrolimus than cyclosporin in SPK recipients. For example, a multicentre matched-pair analysis comparing tacrolimus-with cyclosporin-based therapy in SPK recipients at 18 months post-transplant showed pancreas graft survival rates of 88 versus 71%, renal graft survival rates of 94 versus 77% and patient survival rates of 97 versus 83% (p ≤0.002 for all comparisons). Results of 2 moderate-sized studies of tacrolimus as rescue therapy in SPK recipients showed patient survival rates approaching 100% and pancreas and renal graft survival rates of about 90% (follow-up period ≤1 year after conversion from cyclosporin to tacrolimus).
Intestinal Transplantation
Several reports involving small numbers of patients indicate that tacrolimus is effective in this clinical setting. Data from the International Transplant Registry (n = 170) indicate that, depending on the subgroup of intestinal transplant recipients, tacrolimus-based primary immunosuppression is associated with 1-and 3-year patient survival rates of 59 to 83% and 40 to 47%, respectively, and 1-and 3-year graft survival rates of 51 to 65% and 29 to 38%, respectively. In general, patient and graft survival rates were as good as or better than those achieved with cyclosporin-based regimens. Among cyclosporin recipients, 1-and 3-year patient survival rates were 41 to 57% and 28 to 50%, respectively, and 1-and 3-year graft survival rates were 17 to 44% and 11 to 41%, respectively.
Bone Marrow Transplantation
Three randomised comparative trials have consistently demonstrated a lower incidence of grade II to IV acute graft-versus-host disease (GVHD) with tacrolimus-than cyclosporin-based therapy after allogeneic bone marrow transplantation (BMT). However, the largest of the trials (n = 329) also showed that 2-year overall survival (57 vs 47%; p < 0.05) and disease-free survival (50 vs 41%; p = 0.01) were significantly better among cyclosporin-than tacrolimus-treated patients with haematological malignancy who received BMT from matched sibling donors. These differences were attributed primarily to patients with advanced haematological malignancy at the time of BMT. These survival data in BMT require confirmation. Tacrolimus has also been used with some success in the treatment of patients who developed acute or chronic GVHD or significant toxicity while receiving cyclosporin-based immunosuppressive therapy after BMT, but data are preliminary.
Tolerability
The principal adverse effects associated with tacrolimus treatment include nephrotoxicity, neurotoxicity, disturbances in glucose metabolism, gastrointestinal (GI) disturbance and hypertension. Susceptibility to infection and malignancy is also increased. All of these adverse effects also occur with cyclosporin, although the incidence of some adverse effects differs between the drugs (see later in this section). Tacrolimus is rarely associated with the cyclosporin-specific adverse effects hirsutism, gingivitis and gum hyperplasia, but it may cause alopecia and pruritus in some patients.
Many of the adverse effects of tacrolimus are dose-related; nephrotoxicity, neurotoxicity, glucose metabolism disturbances, GI disturbances and infections may occur more frequently or be more severe at higher whole-blood tacrolimus concentrations. Importantly, these adverse events can often be managed by dosage reductions. Concomitant drugs such as corticosteroids may also contribute to some adverse effects.
In the major trials in patients undergoing liver or kidney transplants, withdrawal rates because of adverse events tended to be higher with tacrolimus than cyclosporin. Nephrotoxicity occurred in as many as half of patients treated with either tacrolimus or cyclosporin. Neurotoxicity associated with tacrolimus most frequently manifests as tremor, headache, insomnia and paraesthesia, and some neurological effects (including tremor and paraesthesia) may be more problematic with tacrolimus than with cyclosporin.
Diabetes mellitus and/or hyperglycaemia also tended to occur more frequently with tacrolimus than with cyclosporin in the major trials in kidney or liver transplant recipients. In 2 large multicentre randomised kidney transplantation trials, the incidence of new-onset type 1 diabetes mellitus was 20 vs 4% in the US trial and 8 vs 2% in the European study. However, about one-quarter to one-third of affected tacrolimus recipients were able to discontinue insulin therapy within 1 year. Furthermore, tacrolimus has generally not been more diabetogenic than cyclosporin in cardiac transplant trials. Also, at least 1 recent study in renal transplant recipients showed a lower incidence of post-transplantation diabetes mellitus with tacrolimus than in previous reports, suggesting that, with more experience, it may be possible to reduce the risk of developing this complication. Other metabolic disturbances that can occur with tacrolimus include hyper-kalaemia and hypomagnesaemia.
A number of studies have shown that tacrolimus has less adverse effect than cyclosporin on lipid profiles and/or the general cardiovascular risk profile. In particular, significantly lower serum levels of total cholesterol, triglycerides and/or low density lipoprotein-cholesterol have been reported with tacrolimus. Hypertension occurred in up to half of patients treated with tacrolimus in major trials, but it was normally mild to moderate in severity, whereas hypertension can be more severe with cyclosporin. In cardiac transplant recipients, hypertension requiring treatment occurred more frequently with cyclosporin-than tacrolimus-based regimens.
GI disturbance, including diarrhoea, nausea and constipation, occurs commonly in patients treated with tacrolimus; diarrhoea is more frequent with tacrolimus than with cyclosporin.
Infection rates were similar in tacrolimus-and cyclosporin-treated groups in the major clinical trials in kidney or liver transplant recipients.
The tolerability profile of tacrolimus in children is generally similar to that in adults. However, children are at increased risk of potentially fatal Epstein-Barr virus-related post-transplant lymphoproliferative disorders (PTLD). The inci-dence of PTLD in paediatric liver transplant recipients may be higher with tacrolimus-than cyclosporin-based immunosuppression. From the reported ex-periences (in >10 patients) of using tacrolimus in primary liver transplantation in children, the incidence of PTLD usually ranged from 3 to 11%, although higher values have been reported. The incidence of PTLD in paediatric patients converted to tacrolimus therapy appears to be higher than that in primary therapy, but this may be associated with high cumulative dosages of immunosuppressive agents required to treat intractable rejection.
The risks of tacrolimus treatment during pregnancy appear to be no greater than those with cyclosporin, and it has been suggested that tacrolimus may be associated with a lower incidence of maternal hypertension or pre-eclampsia.
Dosage and Administration
The dosage recommendations outlined in this section focus on the use of tacrolimus in the US and UK in patients who have undergone liver or kidney transplantation. Although treatment regimens can vary between countries and individual transplantation centres, it is likely that tacrolimus is used in a similar manner for immunosuppression following other types of transplantation.
Whenever possible, tacrolimus should be initiated using the oral route of administration. For patients unable to take tacrolimus orally, therapy may be initiated by continuous intravenous infusion. In the US, the recommended intravenous starting dose is 0.03 to 0.05 mg/kg/day for adults receiving liver or kidney transplantation and for children receiving liver transplantation; no specific recommendation for paediatric kidney transplantation is provided in US prescribing information. In the UK, initial intravenous dose recommendations for adults are 0.01 to 0.05 mg/kg/day for liver and 0.05 to 0.10 mg/kg/day for kidney transplantation; corresponding recommendations for children are 0.05 mg/kg/day for liver and 0.1 mg/kg/day for kidney transplantation. Conversion from intravenous to oral therapy should occur as soon as is clinically feasible, usually within 2 to 3 days. Whether administered by the oral or intravenous route, the initial dose of tacrolimus should begin approximately 6 hours after the completion of liver transplant surgery and within 24 hours of kidney transplantation surgery.
Oral tacrolimus is administered in 2 divided daily doses at 12-hour intervals. In adults, the recommended starting oral dosage of tacrolimus as primary immunosuppression is 0.10 to 0.15 mg/kg/day (US) or 0.10 to 0.20 mg/kg/day (UK) for liver transplantation and 0.2 mg/kg/day (US) or 0.15 to 0.30 mg/kg/day (UK) for kidney transplantation. Initial recommended dosage in children receiving liver transplantation is 0.15 to 0.20 mg/kg/day (US) or 0.3 mg/kg/day (UK). In the UK, 0.3 mg/kg/day is the recommended initial dose of tacrolimus in paediatric renal transplant recipients; US prescribing information does not provide a corresponding recommendation for this patient population.
During maintenance therapy the dose of tacrolimus can often be reduced. In general, children require higher doses than adults to achieve similar blood concentrations of tacrolimus. Likewise, African-American patients typically require higher tacrolimus doses than Caucasian patients (at least in kidney transplantation) to achieve similar blood concentrations of the drug. Patients with hepatic or renal dysfunction should receive doses at the lowest value of the recommended intravenous and oral dosage ranges (and further dosage reductions may be required).
When tacrolimus is used as rescue therapy in patients not responding to (or not tolerating) cyclosporin-based therapy, treatment should begin with the same initial dosage as for primary therapy in that particular allograft (UK recommendation). Tacrolimus should not be started until approximately 24 hours after discontinuation of cyclosporin therapy.
Tacrolimus is a well-known potent immunosuppressant agent, which has various drug-drug or food-drug interactions. Previously, we found a renal transplant recipient who increased tacrolimus blood concentrations after ingestion of pomelo as a rare case. So, we investigated the effect of pomelo after its administration for one day or 3 consecutive days on the pharmacokinetics of tacrolimus in rats. We also confirmed the effects of grapefruit, turmeric, and ginger. The tacrolimus blood concentrations of the rats pre-treated with 100% pomelo juice were significantly higher than those pre-treated with water. On the other hand, the tacrolimus blood concentrations of the rats pre-treated with 50% pomelo juice were not significantly different from those pre-treated with water. The pomelo-tacrolimus interaction showed concentration dependency. Even low concentration of pomelo juice could enhance the blood concentrations of tacrolimus by repeated administration. The inhibitory effect of 100% pomelo juice disappeared 3 days after intake. The AUC values of tacrolimus in the rats pre-treated with grapefruit juice, ginger juice, and turmeric juice were significantly larger than those pre-treated with water. We could confirm the pomelo-tacrolimus interaction, which we discovered in a case study, quantitatively. We newly found the influence of turmeric and ginger on tacrolimus pharmacokinetics, comparable to pomelo.
Tacrolimus (Tac) is widely used to prevent allograft rejection after liver transplantation. We found that the concentration of Tac in blood was significantly increased in liver transplant patients who were receiving Schisandra sphenanthera extract (SchE). The objective of this study was to determine the effect of SchE on the concentration of Tac in the blood of liver transplant patients.
Patients were initially administered Tac (first phase) and then SchE was provided (second phase). During the first phase of treatment, 46 patients received the same oral dose of Tac. In the second phase of treatment, 21 patients (Group A) received the same dose of Tac and 25 patients (Group B) received a lower dose of Tac. The concentration of Tac in the blood and the biochemical indices of liver function, as well as symptoms of Tac-related toxicity, were determined, and 14 patients were selected for a pharmacokinetic study.
After co-administration of Tac and SchE, the average increase in the mean concentration of Tac in the blood was 339% and 262% in Groups A and B, respectively. The liver function indices were decreased significantly (p < 0.01); whereas the average increase of Cmax, AUC0-12 and AUMC0-12 of Tac was 183%, 212% and 227%, respectively. Tac-associated side-effects, such as diarrhoea and agitation, decreased significantly in all patients, but the incidence of other side-effects did not change significantly.
SchE markedly increased the concentration of Tac in the blood of liver transplant patients, improved liver function and reduced the incidence of Tac-associated side-effects.
The interactions between grapefruit juice (GFJ) and tacrolimus (FK506) metabolism remain obscure. The aim of this prospective study was to explore the effect of GFJ on the blood concentration of FK506 in liver transplant patients.
Thirty liver transplant patients were enrolled in the study 1 month post-transplant and randomly divided into three equal-sized groups. Group A patients were treated with the standard FK506-based immunosuppressant regimen only and therefore served as the control; group B and C patients were treated with the standard FK506-based immunosuppressant regimen as well as one of two different kinds of GFJ, respectively. The blood concentrations of FK506 on the seventh day after GFJ intake were compared within each group and among groups. The dose of FK506 was adjusted depending on the valley concentration measured to a treatment window.
The blood concentration of FK506 in both group B and group C patients was significantly enhanced, by 1.56 +/- 0.95 and 10.33 +/- 5.59 ng/ml, respectively, following the administration of GFJ for 1 week (compared with the concentration at the start of the experiment in each group; p < 0.05). However, at the end time point, the blood concentration of FK506 in group C patients was significantly increased (p < 0.05) relative to that of the control patients, while this was not the case in group B patients (p > 0.05). Group C patients could be treated with a smaller dose of FK506 (decreased by 2.3 +/- 1.3 mg/day for all patients; p = 0.011), amounting to a decrease in drug costs of approximately $8.70 +/- 5.60/day (p = 0.011).
In the setting of a controlled clinical study, the co-administration of GFJ with FK506 increased the bioavailability of FK506. However, the concentration of tacrolimus should be closely monitored and the dose adjusted to the treatment window.
Curcumin (diferuloylmethane), a yellow pigment in the spice turmeric (also called curry powder), has been used for centuries as a treatment for inflammatory diseases. Extensive research within the past two decades has shown that curcumin mediates its anti-inflammatory effects through the downregulation of inflammatory transcription factors (such as nuclear factor kappaB), enzymes (such as cyclooxygenase 2 and 5 lipoxygenase) and cytokines (such as tumor necrosis factor, interleukin 1 and interleukin 6). Because of the crucial role of inflammation in most chronic diseases, the potential of curcumin has been examined in neoplastic, neurological, cardiovascular, pulmonary and metabolic diseases. The pharmacodynamics and pharmacokinetics of curcumin have been examined in animals and in humans. Various pharmacological aspects of curcumin in vitro and in vivo are discussed in detail here.
With increasing numbers of solid organ and hematopoietic stem cell transplantations being performed, there have been significant increases in the use of immunosuppressive agents such as cyclosporine and tacrolimus. Posterior reversible encephalopathy syndrome (PRES) is a serious complication of immunosuppressive therapy use following solid organ or stem cell transplants. Clinical findings including headache, mental status changes, focal neurological deficits, and/or visual disturbances. Associated with these are characteristic imaging features of subcortical white matter lesions on computed tomography (CT) or magnetic resonance imaging (MRI). The changes in the subcortical white matter are secondary to potentially reversible vasogenic edema, although conversion to irreversible cytotoxic edema has been described. These imaging findings predominate in the territory of the posterior cerebral artery. Many studies have shown that the neurotoxicity associated with tacrolimus may occur at therapeutic levels. In most cases of PRES, the symptom complex is reversible by reducing the dosage or withholding the drug for a few days. While PRES is an uncommon complication, it is associated with significant morbidity and mortality if it is not expeditiously recognized. MRI represents the most sensitive imaging technique for recognizing PRES. This report highlights the value of MRI in prompt recognition of this entity, which offers the best chance of avoiding long-term sequelae.
Recent evidence suggests that the potent constrictor peptide, endothelin (ET) has a mediating role in cyclosporine A (CsA)-related renal vasoconstriction. However, the nature of the CsA-ET interaction and effect on the renal vasculature is uncertain. The purpose of the present study was twofold: (a) to determine if CsA exposure caused direct local release of ET from the endothelium of the renal microvasculature and (b) to determine if locally generated ET has paracrine effects on the underlying vascular smooth muscle to induce vasoconstriction. Experiments were performed in isolated rat renal arterioles. First it was determined that both afferent arteriole (AA) and efferent arteriole (EA) exhibited concentration-dependent decreases in lumen diameter to increasing molar concentrations of CsA. The AA was more sensitive to the vasoconstrictive effects of CsA than the EA. Next, the blocking effect of a recently synthesized putative ETA receptor antagonist was verified in both the AA and EA, where it was found that the cyclic peptide cyclo D-Asp-L-Pro-D-Val-L-Leu-D-Trp totally inhibited the vasoconstriction observed with ET addition. Finally, the role of locally stimulated ET in CsA-induced vasoconstriction was tested by determining the effect of the ETA receptor antagonist on CsA-induced AA and EA constriction. In the AA the vasoconstrictor effect of 10(-11) M CsA was completely blocked by the ETA receptor antagonist. However, in contrast to AA, 10(-11) M CsA in EA in the presence of the ETA receptor antagonist decreased EA lumen diameter by a mean of 41% from baseline (4.80 +/- 0.75 microns vs 7.80 +/- 0.84 microns, P < 0.05). This change in lumen diameter was similar to that induced by CsA alone. These data suggest that CsA directly constricts renal microvessels. This effect is mediated by ET in the AA but not the EA.
Tacrolimus, a novel macrocyclic lactone with potent immunosuppressive properties, is currently available as an intravenous formulation and as a capsule for oral use, although other formulations are under investigation. Tacrolimus concentrations in biological fluids have been measured using a number of methods, which are reviewed and compared in the present article. The development of a simple, specific and sensitive assay method for measuring concentrations of tacrolimus is limited by the low absorptivity of the drug, low plasma and blood concentrations, and the presence of metabolites and other drugs which may interfere with the determination of tacrolimus concentrations. Currently, most of the pharmacokinetic data available for tacrolimus are based on an enzyme-linked immunosorbent assay method, which does not distinguish tacrolimus from its metabolites. The rate of absorption of tacrolimus is variable with peak blood or plasma concentrations being reached in 0.5 to 6 hours; approximately 25% of the oral dose is bioavailable. Tacrolimus is extensively bound to red blood cells, with a mean blood to plasma ratio of about 15; albumin and alpha 1-acid glycoprotein appear to primarily bind tacrolimus in plasma. Tacrolimus is completely metabolised prior to elimination. The mean disposition half-life is 12 hours and the total body clearance based on blood concentration is approximately 0.06 L/h/kg. The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of several drugs. Various factors that contribute to the large inter- and interindividual variability in the pharmacokinetics of tacrolimus are reviewed here. Because of this variability, the narrow therapeutic index of tacrolimus, and the potential for several drug interactions, monitoring of tacrolimus blood concentrations is useful for optimisation of therapy and dosage regimen design.
FK506 (tacrolimus) is a safe and effective immunosuppressant for the prevention of organ rejection after organ transplantation. FK506 has a relatively narrow therapeutic index and the correlation of dose to blood concentration is poor as a result of moderate variability in pharmacokinetic parameters between patients. Therapeutic monitoring of whole blood FK506 drug concentrations has been used in an effort to determine whether a relationship exists between concentrations of FK506 in the blood and the development of toxicity or the risk for organ rejection. An analysis of the relationship between FK506 blood levels and the occurrence of toxicity and rejection was carried out using data from four recent clinical trials. Trough FK506 levels within a 7-day window before the onset of rejection or toxicity were analyzed using logistic regression models. In kidney transplant patients (n=92), a significant correlation between FK506 levels and the incidence of both toxicity (P=0.01) and rejection (P=0.02) was seen. In liver transplant patients from three clinical trials, FK506 levels correlated well with the incidence of toxicity (P < or = 0.01); however, there was no significant relationship between FK506 levels and the incidence of rejection. It is concluded that therapeutic monitoring of whole blood FK506 levels may be useful for minimizing the risks of both toxicity and rejection in kidney transplant patients and for minimizing the risk of toxicity in liver transplant recipients.
Unlabelled:
Tacrolimus (FK-506) is an immunosuppressant agent that acts by a variety of different mechanisms which include inhibition of calcineurin. It is used as a therapeutic alternative to cyclosporin, and therefore represents a cornerstone of immunosuppressive therapy in organ transplant recipients. Tacrolimus is now well established for primary immunosuppression in liver and kidney transplantation, and experience with its use in other types of solid organ transplantation, including heart, lung, pancreas and intestinal, as well as its use for the prevention of graft-versus-host disease in allogeneic bone marrow transplantation (BMT), is rapidly accumulating. Large randomised nonblind multicentre studies conducted in the US and Europe in both liver and kidney transplantation showed similar patient and graft survival rates between treatment groups (although rates were numerically higher with tacrolimus- versus cyclosporin-based immunosuppression in adults with liver transplants), and a consistent statistically significant advantage for tacrolimus with respect to acute rejection rate. Chronic rejection rates were also significantly lower with tacrolimus in a large randomised liver transplantation trial, and a trend towards a lower rate of chronic rejection was noted with tacrolimus in a large multicentre renal transplantation study. In general, a similar trend in overall efficacy has been demonstrated in a number of additional clinical trials comparing tacrolimus- with cyclosporin-based immunosuppression in various types of transplantation. One notable exception is in BMT, where a large randomised trial showed significantly better 2-year patient survival with cyclosporin over tacrolimus, which was primarily attributed to patients with advanced haematological malignancies at the time of (matched sibling donor) BMT. These survival results in BMT require further elucidation. Tacrolimus has also demonstrated efficacy in various types of transplantation as rescue therapy in patients who experience persistent acute rejection (or significant adverse effect's) with cyclosporin-based therapy, whereas cyclosporin has not demonstrated a similar capacity to reverse refractory acute rejection. A corticosteroid-sparing effect has been demonstrated in several studies with tacrolimus, which may be a particularly useful consideration in children receiving transplants. The differences in the tolerability profiles of tacrolimus and cyclosporin may well be an influential factor in selecting the optimal treatment for patients undergoing organ transplantation. Although both drugs have a similar degree of nephrotoxicity, cyclosporin has a higher incidence of significant hypertension, hypercholesterolaemia, hirsutism and gingival hyperplasia, while tacrolimus has a higher incidence of diabetes mellitus, some types of neurotoxicity (e.g. tremor, paraesthesia), diarrhoea and alopecia.
Conclusion:
Tacrolimus is an important therapeutic option for the optimal individualisation of immunosuppressive therapy in transplant recipients.
Tacrolimus, an immunosuppressive agent, is widely used in patients after transplantation to prevent allograft rejection. Because tacrolimus has a narrow therapeutic range, it is essential to carefully control the blood level. It has been demonstrated that tacrolimus is metabolized mainly by cytochrome P-450 (CYP) 3A4, and that tacrolimus is a substrate of P-glycoprotein.
This article reports a case of considerable increase in the blood level of tacrolimus after the intake of pomelo in a renal transplant recipient.
Pomelo may increase the blood concentration of tacrolimus by inhibiting CYP 3A4, P-glycoprotein, or both.
Patients taking drugs such as tacrolimus or cyclosporine, which have their kinetics affected by grapefruit juice, should avoid pomelo and other grapefruit-related citrus fruits.
The purpose of this pharmacokinetic study was to determine whether the relative oral bioavailability of tacrolimus is increased with concomitant administration of clotrimazole. Pharmacokinetic studies were conducted in 6 adult kidney transplant patients receiving tacrolimus therapy. Pharmacokinetic profiling was performed by blood sampling over 12 hours before and after the administration of a 5-day course of clotrimazole. Tacrolimus whole-blood concentrations were determined by microparticle enzyme immunoassay. Noncompartmental pharmacokinetic analysis was conducted using WinNonLin, Standard Edition, Version 1.1. Concomitant administration of clotrimazole more than doubled the relative oral bioavailability of tacrolimus. The mean AUC0-12 of tacrolimus was increased 250% with clotrimazole (467.0 +/- 170.0 ng.h/mL versus 188.7 +/- 50.2 ng.h/mL; P = 0.002). Tacrolimus blood trough concentrations also more than doubled with coadministration of clotrimazole (27.7 +/- 10.4 ng/mL versus 11.6 +/- 4.0 ng/mL; P = 0.003). Mean Cmax was significantly increased with clotrimazole (70.7 +/- 34.7 ng/mL versus 27.4 +/- 11.1 ng/mL, P = 0.01). Tmax decreased from 3.2 +/- 1.6 hours to 1.9 +/- 1.0 hours (P = NS). In addition, the apparent oral clearance decreased 60% with coadministration of clotrimazole (median oral clearance 0.16 L/h/kg versus 0.40 L/h/kg; P = 0.03). Thus, clotrimazole causes a significant increase in the relative oral bioavailability, Tmax, and trough concentration of tacrolimus. Tacrolimus levels should be monitored following initiation or discontinuation of clotrimazole to minimize toxicity or precipitation of an acute rejection episode due to subtherapeutic levels.
The aim of this study was to evaluate whether curcumin could modulate P-glycoprotein (P-gp) and CYP3A expression, and in turn modify the pharmacokinetic profiles of P-gp and CYP3A substrates in male Sprague-Dawley rats. Intragastric gavage of the rats with 60 mg/kg curcumin for 4 consecutive days led to a down-regulation of the intestinal P-gp level. There was a concomitant upregulation of hepatic P-gp level, but the renal P-gp level was unaffected. Curcumin also attenuated the CYP3A level in the small intestine but induced CYP3A expression in the liver and kidney. Regular curcumin consumption also caused the C(max) and area under the concentration-time curve (AUC(0-8) and total AUC) of peroral celiprolol (a P-gp substrate with negligible cytochrome P450 metabolism) at 30 mg/kg to increase, but the apparent oral clearance (CL(oral)) of the drug was reduced. Similarly, rats treated with curcumin for 4 consecutive days showed higher AUC (AUC(0-4) and total AUC) and lower CL(oral) for peroral midazolam (a CYP3A substrate that does not interact with the P-gp) at 20 mg/kg in comparison with vehicle-treated rats. In contrast, curcumin administered 30 min before the respective drug treatments did not significantly modify the pharmacokinetic parameters of the drugs. Analysis of the data suggests that the changes in the pharmacokinetic profiles of peroral celiprolol and midazolam in the rat model were contributed mainly by the curcumin-mediated down-regulation of intestinal P-gp and CYP3A protein levels, respectively.
Tacrolimus (FK506), an immunosuppressive drug, is co-medicated with multiple drugs under clinical conditions. Tacrolimus is highly lipophilic and is excreted from the body after receiving extensive metabolism. Due to its narrow therapeutic window following organ transplantation, tacrolimus requires therapeutic drug monitoring by an enzyme immunoassay using the monoclonal antibody raised against tacrolimus. Therefore, metabolism studies including drug-drug interaction and metabolite identification studies are essential for the efficient development and clinically optimal usage of this drug. Tacrolimus was metabolized by the cytochrome P450 (CYP) 3A subfamily. Metabolic drug-drug interaction studies were conducted to provide information regarding the optimal usage of tacrolimus, and its metabolism was inhibited by known CYP3A inhibitors such as ketoconazole, cyclosporine A, and nifedipine. Recent reports on clinical pharmacokinetics indicate that dose levels of tacrolimus need to be adjusted in transplant patients with CYP3A5 polymorphism.