European Journal of Drug Metabolism and Pharmacokinetics (EUR J DRUG METAB PH)

Publications in this journal

• Article: Effect of natural borneol on the pharmacokinetics and distribution of nimodipine in mice.

  Chun Wu, Qiongfeng Liao, Meicun Yao, Xinjun Xu, Yuting Zhou, Xueying Hou, Zhiyong Xie
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  ABSTRACT: The purpose of this study was to investigate the effect of natural borneol (NB) on the pharmacokinetics and distribution of nimodipine in mice. A single dose of nimodipine was administered intravenously (2 mg/kg) to mice pretreated with NB (250 mg/kg) or vehicle. Blood as well as brain, liver, and kidney tissue samples were collected at 5, 10, 20, 40, and 60 min post-dose nimodipine. The concentrations of nimodipine in plasma and tissues were determined by ultra performance liquid chromatography (UPLC) coupled with UV detection, and the pharmacokinetic parameters were calculated based on non-compartmental analysis. NB increased the plasma AUC5-60 min by 26 % compared to the vehicle. In addition, brain concentrations of nimodipine in NB-treated mice were significantly higher than those in control mice with the increased AUC5-60 min by 30 %. In liver and kidney, NB also caused 26 and 47 % increase in AUC5-60 min, respectively. These results implicated that NB may inhibit the metabolism or elimination of nimodipine and enhance its distribution in brain and kidney tissue.
  European Journal of Drug Metabolism and Pharmacokinetics 05/2013;
• Article: Is pomegranate juice a potential perpetrator of clinical drug-drug interactions? Review of the in vitro, preclinical and clinical evidence.

  Nuggehally R Srinivas
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  ABSTRACT: The area of fruit juice-drug interaction has received wide attention with numerous scientific and clinical investigations performed and reported for scores of drugs metabolized by CYP3A4/CYP2C9. While grapefruit juice has been extensively studied with respect to its drug-drug interaction potential, numerous other fruit juices such as cranberry juice, orange juice, grape juice, pineapple juice and pomegranate juice have also been investigated for its potential to show drug-drug interaction of any clinical relevance. This review focuses on establishing any relevance for clinical drug-drug interaction potential with pomegranate juice, which has been shown to produce therapeutic benefits over a wide range of disease areas. The review collates and evaluates relevant published in vitro, preclinical and clinical evidence of the potential of pomegranate juice to be a perpetrator in drug-drug interactions mediated by CYP3A4 and CYP2C9. In vitro and animal pharmacokinetic data support the possibility of CYP3A4/CYP2C9 inhibition by pomegranate juice; however, the human relevance for drug-drug interaction was not established based on the limited case studies.
  European Journal of Drug Metabolism and Pharmacokinetics 05/2013;
• Article: Integration of preclinical and clinical knowledge to predict intravenous PK in human: Bilastine case study.

  Valvanera Vozmediano, Ignacio Ortega, John C Lukas, Ana Gonzalo, Monica Rodriguez, Maria Luisa Lucero
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  ABSTRACT: Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes.
  European Journal of Drug Metabolism and Pharmacokinetics 04/2013;
• Article: Effect of borneol on cytochrome P450 3A enzyme and midazolam pharmacokinetics in rats.

  Rong Zhang, Sui-Qing Mi, Ning-Sheng Wang
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  ABSTRACT: Borneol is a commonly used herbal medication in China and Japan. Previous studies have indicated that borneol could reduce the plasma concentrations of oneself and concomitant drugs, and its first-pass metabolism could be catalyzed by the cytochrome P450 3A (CYP3A) enzyme as well. The impact of borneol on CYP3A activity and efficacy in influencing the pharmacokinetics of co-administrated drugs is currently unknown. Therefore, the purpose of the current study is to investigate the effect of borneol on CYP3A enzyme in vivo. After treatment with borneol twice daily for 3 days, rat liver microsomes were exposed to probe substrates to determine CYP3A enzyme activity, protein, and RNA harvested using microsomal testosterone 6β-hydroxylation as a marker of enzyme activity. To verify the result, the effect of borneol on the pharmacokinetics of the CYP3A model substrate midazolam was further examined. The results showed that borneol treatment had increased CYP3A expression at the mRNA, protein, and activity (testosterone 6β hydroxylase activity) level in rat liver microsomes. In addition, borneol accelerated the metabolism of midazolam, which was consistent with the enhancement in CYP3A metabolic capacity. The hepatic clearance (Cl) of midazolam injected via the caudal vein in rats following borneol co-administration was higher; however, the area under the curve (AUC0-∞) was lower than the solvent. Hence, it was proposed that borneol could increase the metabolic activity of the CYP3A enzyme, which might cause drug-drug interactions in humans when using Chinese herbal or Western medicine with borneol.
  European Journal of Drug Metabolism and Pharmacokinetics 04/2013;
• Article: Impact of physiochemical properties on pharmacokinetics of protein therapeutics.

  Rajan Swami, Aliasgar Shahiwala
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  ABSTRACT: Physicochemical properties, such as molecular weight, size, partition coefficient, acid dissociation constant and solubility have a great impact on pharmacokinetics of traditional small molecule drugs and substantially used in development of small drugs. However, predicting pharmacokinetic fate (absorption, distribution, metabolism and elimination) of protein therapeutics from their physicochemical parameters is extremely difficult due to the macromolecular nature of therapeutic proteins and peptides. Their structural complexity and immunogenicity are other contributing factors that determine their biological fate. Therefore, to develop generalized strategies concerning development of therapeutic proteins and peptides are highly challenging. However, reviewing the literature, authors found that physiochemical properties, such as molecular weight, charge and structural modification are having great impact on pharmacokinetics of protein therapeutics and an attempt is made to provide the major findings in this manuscript. This manuscript will serve to provide some bases for developing protein therapeutics with desired pharmacokinetic profile.
  European Journal of Drug Metabolism and Pharmacokinetics 04/2013;
• Article: Pharmacokinetic analysis of doxifluridine and its metabolites, 5-fluorouracil and 5-fluorouridine, after oral administration in beagle dogs.

  In-Hwan Baek, Byung-Yo Lee, Min-Soo Kim, Kwang-Il Kwon
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  ABSTRACT: Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR) is a fluoropyrimidine derivative that is activated preferentially in malignant cells by thymidine phosphorylase to form 5-fluorouracil (5-FU). The purpose of this study was to investigate the pharmacokinetic properties of doxifluridine and its two major metabolites, 5-FU, and 5-fluorouridine (5-FUrd), in beagle dogs following a single oral administration of 200 mg doxifluridine capsule (Furtulon(®)). After the administration of 200 mg of Furtulon to 23 beagle dogs, the plasma concentrations of doxifluridine, 5-FU, and 5-FUrd were measured simultaneously, using LC-MS/MS. The parent-metabolite compartment model with first-order absorption and Michaelis-Menten kinetics described the pharmacokinetics of doxifluridine, 5-FU, and 5-FUrd. Michaelis-Menten kinetics sufficiently explained the generation and elimination processes of 5-FU and 5-FUrd. The studies described here are the first to evaluate the relationship between pharmacokinetics of doxifluridine and its metabolites in dogs, and these findings will help in understanding the toxicity mechanism of doxifluridine.
  European Journal of Drug Metabolism and Pharmacokinetics 04/2013;
• Article: Disposition of ceftriaxone in hepatopathic goats following single-intramuscular dosing.

  Tapas Kumar Sar, Tapan Kumar Mandal, Pabitra Hriday Patra, Indranil Samanta
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  ABSTRACT: Hepatopathy sometimes may interfere with metabolism and/or elimination of drugs which undergo major hepatic clearance. Twelve healthy goats were equally divided into two groups (I and II) and hepatopathy was induced by carbontetrachloride in the second group (group II). A single dose of ceftriaxone at 50 mg/kg was administered to each group intramuscularly. Disposition of ceftriaxone in plasma of healthy goats showed a typical absorption-reabsorption phase. However, the reabsorption phase was totally absent in hepatopathic goats and the disposition of ceftriaxone showed only absorption and distribution/elimination phase. The drug persisted in plasma for 6 h in hepatopathic animals, whereas the drug can only be detected up to 2 h in healthy animals indicating longer persistence of ceftriaxone in the former group. Ceftizoxime, the active metabolite of ceftriaxone was available in urine of group I animals, whereas only ceftriaxone was detected in the urine of hepatopathic animals suggesting impairment of metabolism of the parent drug in hepatopathy. Therefore, the reabsorption and metabolism of ceftriaxone in goats should be taken into consideration for drug monitoring.
  European Journal of Drug Metabolism and Pharmacokinetics 04/2013;
• Article: Analysis of thiopurine S-methyltransferase phenotype-genotype in a Tunisian population with Crohn's disease.

  Lynda Ben Salah, Mouna Belkhiria El Haj Amor, Chahra Chbili, Saida Khlifi, Neila Fathallah, Iheb Bougmiza, Elhem Ben Jazia, Nicole Houdret, Chaker Ben Salem, Saad Saguem
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  ABSTRACT: This study was conducted to investigate the thiopurine S-methyltransferase TPMT activity distribution and gene mutations in Tunisian population with positive diagnostic for Crohn's disease. TPMT activity was measured in Tunisian population (n = 88) by a high performance liquid chromatography assay. Polymerase chain reaction-based methods were used to determine the frequency of TPMT mutant alleles TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C. TPMT activity was normally distributed, ranging from 4.58 to 35.27 nmol/(h ml) RBC with a mean of 18.67 ± 7.10 nmol/(h ml) RBC. Seven TPMT*3A heterozygotes and one TPMT*3C homozygote were found in 88 patients, with allele frequencies of 0.039 and 1.13, respectively. TPMT*3A and the TPMT*3C, which cause the largest decrease in enzyme activity, were both variant alleles detected in the Tunisian population.
  European Journal of Drug Metabolism and Pharmacokinetics 04/2013;
• Article: Effective concentration-based serum pharmacodynamics for antifungal azoles in a murine model of disseminated Candida albicans infection.

  Katsuyuki Maki, Shuji Kaneko
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  ABSTRACT: An assessment of the effective in vivo concentrations of antifungal drugs is important in determining their pharmacodynamics, and therefore, their optimal dosage regimen. Here we establish the effective in vivo concentration-based pharmacodynamics of three azole antifungal drugs (fluconazole, itraconazole, and ketoconazole) in a murine model of disseminated Candida albicans infection. A key feature of this study was the use of a measure of mycelial (m) growth rather than of yeast growth, and pooled mouse sera rather than synthetic media as a growth medium, for determining the minimum inhibitory concentrations (MICs) of azoles for C. albicans (denoted serum mMICs). The serum mMIC assay was then used to measure antifungal concentrations and effects as serum antifungal titers in the serum of treated mice. Both serum mMIC and sub-mMIC values reflected the effective in vivo serum concentrations. Supra-mMIC and mMIC effects exhibited equivalent efficacies and were concentration-independent, while the sub-mMIC effect was concentration-dependent. Following administration of the minimum drug dosage that inhibited an increase in mouse kidney fungal burden, the duration periods of these effects were similar for all drugs tested. The average duration of either the mMIC effect including the supra-mMIC effect, the sub-mMIC effect, or the post-antifungal effect (PAFE) were 6.9, 6.5 and 10.6 h, respectively. Our study suggests that the area under the curve for serum drug concentration versus time, between the serum mMIC and the sub-mMIC, and exposure time above the serum sub-mMIC after the mMIC effect, are major pharmacodynamic parameters. These findings have important implications for effective concentration-based pharmacodynamics of fungal infections treated with azoles.
  European Journal of Drug Metabolism and Pharmacokinetics 03/2013;
• Article: Influence of the multidrug transporter P-glycoprotein on the intracellular pharmacokinetics of vandetanib.

  C Jovelet, A Deroussent, S Broutin, A Paci, R Farinotti, J M Bidart, S Gil
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  ABSTRACT: Efflux transporters play an important role in the resistance of tumor cells against anticancer agents. Interaction between these transporters, including P-glycoprotein (P-gp), and drugs might influence their pharmacological properties and toxicities. The aim of this study was to investigate whether vandetanib (Caprelsa®), a small tyrosine kinase inhibitor, could interact with the multidrug transporter P-gp. Interaction of vandetanib with the P-gp was investigated using the parental cell line (IGROV1) and the P-gp doxorubicin-resistant (IGROV1-DXR) cell line, derived from the parental drug-sensitive IGROV1 cells. Cytotoxicity tests were assessed in both cell lines to examine the impact of P-gp on the cell survival after a vandetanib treatment. The effects of P-gp on vandetanib intracellular pharmacokinetics were investigated. To this aim, we developed a quantitative liquid chromatography tandem mass spectrometry to quantify vandetanib in cell medium. Results showed that overexpression of P-gp confers resistance to vandetanib in the IGROV1-DXR cell line. Using a LC-MS/MS assay validated in cell medium, cellular pharmacokinetic studies revealed that in cells overexpressing the P-gp intracellular concentrations of vandetanib were decreased compared to parental cell line. For the first time, vandetanib is described as a substrate of P-gp. In tumor cells, P-gp could be responsible for cellular resistance to vandetanib. It may be relevant to the clinical efficacy of vandetanib. Moreover, interaction of vandetanib with P-gp could modify the pharmacodynamics of other conventional chemotherapeutics, substrates of P-gp. It could impact on the overall response to anticancer therapy.
  European Journal of Drug Metabolism and Pharmacokinetics 02/2013;
• Article: Genotype-phenotype correlation of cytochrome P450 2C9 polymorphism in Indian National Capital Region.

  Ekta Varshney, Nilanjan Saha, Monika Tandon, Vikesh Shrivastava, Shakir Ali
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  ABSTRACT: Identification of polymorphism of cytochrome P450 2C9 (CYP2C9) enzymes in different ethnic populations is important to understand the differences in clinical responses to drugs. This study determines the CYP2C9 genetic polymorphism in Indian National Capital Region and correlates the phenotype-genotype. Losartan (25 mg) was administered to 107 volunteers to assess CYP2C9 activity, and, on the basis of results, volunteers were categorized as rapid and poor metabolizers. Molecular typing of CYP2C9*1 (wild type), CYP2C9*2, and CYP2C9*3 (the most common variant) was carried out by single-base primer extension technology for 37 subjects, of which 9 were poor metabolizers, and 28 were rapid metabolizers. 14.28 % of the studied population was identified as poor metabolizer for the category of drugs metabolized by CYP2C9. Significant difference was observed between the mean ratio (drug/metabolite) of poor (11.38 ± 5.88) and rapid (1.18 ± 1.11) drug metabolizers. The study suggests that phenotyping of CYP2C9 is desirable before enrollment of subjects for clinical trials or for deciding drug dose regimen as 14.28 % of study population was found to be poor metabolizer for the category of drugs metabolized by CYP2C9. This study establishes phenotype-genotype correlation, and proposes to use genotyping or phenotyping to evaluate the status of drug metabolizing capacity of CYP2C9 as a primary screening procedure before enrolling subjects in clinical trials or in clinical practice.
  European Journal of Drug Metabolism and Pharmacokinetics 02/2013;
• Article: Interactions between new quinolone antibacterials and diagnostic drug containing manganese.

  Moeko Hosono, Haruko Yokoyama, Risa Takayanagi, Yasuhiko Yamada
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  ABSTRACT: A diagnostic drug containing manganese chloride tetrahydrate as a major ingredient is available since 2006. It is used in magnetic resonance imaging as a negative contrast medium for magnetic resonance cholangiopancreatography of the gastrointestinal tract. However, there is no report regarding interaction between manganese and new quinolone antibacterials. We investigated the interactions between new quinolone antibacterials and a diagnostic drug containing manganese in vitro. We evaluated the rate of formation of chelate complex by reacting new quinolone antibacterials (levofloxacin, ofloxacin, ciprofloxacin) with a diagnostic drug containing manganese. The EC(50) values of the formation of chelate complex for levofloxacin, ofloxacin, and ciprofloxacin were 5.14 ± 0.14, 5.29 ± 0.14, and 0.96 ± 0.04 mM, respectively. The rates of formation of chelate complex by levofloxacin, ofloxacin, and ciprofloxacin in a reaction with the diagnostic drug were 17.0, 18.9, and 55.5 % in clinical condition, respectively. Our results suggest that a complex of each antibacterial and manganese was formed, with ciprofloxacin causing the strongest interaction. In addition, our findings indicate that the degree of interaction may be an important problem in clinical settings with concomitant administration of a new quinolone antibacterial and diagnostic drug containing manganese.
  European Journal of Drug Metabolism and Pharmacokinetics 02/2013;
• Article: Pharmacokinetic disposition of anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in rats and dogs.

  Shinji Furuta, Miyuki Tamura, Hiroko Hirooka, Yukie Mizuno, Mika Miyoshi, Yoshiyuki Furuta
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  ABSTRACT: The pharmacokinetic disposition of anagliptin, an orally active and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated in male rats and dogs. Anagliptin was well absorbed in dogs (70.4 %) and moderately to well absorbed in rats ranging from 38.1 to 85.5 % depending on the dose. In situ testing indicated that anagliptin absorption from rat intestine was apparently limited by P-glycoprotein. The absorbed radioactivity was distributed rapidly throughout the body, and high levels of radioactivity were found in the tissues expressing DPP-4 at high levels, especially small intestine, kidney and liver. In both species, the major circulating component was unchanged anagliptin; major circulating metabolites were M1 resulting from hydrolysis of the cyano group and M6 and M7, both of which resulting from the oxidation-cleavage of the methylene function adjacent to the amine. After intravenous dosing, urinary excretion of radioactivity was the major route of elimination for rats (64.6 %) and dogs (66.2 %), and biliary excretion was demonstrated to be an important pathway in rats (25.2 %). The total recovery was good (97.5-99.5 %) and most of the radioactivity was excreted by 24 h in both species. The renal clearance of unbound anagliptin in rats (91.7 ml/min/kg) was much higher than the glomerular filtration rate, indicative of active renal elimination.
  European Journal of Drug Metabolism and Pharmacokinetics 02/2013;
• Article: Pharmacokinetic study of multiple active constituents after oral gavage of Guizhi decoction in rats using a LC-MS/MS method.

  Yingrong Chen, Chenglu Gao, Yueming Ma, Furong Qiu
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  ABSTRACT: Guizhi decoction (GZD) is a classic traditional Chinese medicine formula, clinically used for the treatment of influenza, common cold, and other pyretic conditions. A sensitive, specific, and validated liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed to investigate the pharmacokinetic properties of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid in rat. After single dose oral administration of 7.9 g extract/kg body weight GZD in rats, plasma concentrations of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid were measured by LC-MS/MS. Pharmacokinetic parameters were calculated from the plasma concentration-time data. The values of AUC(0-t), half-life (t (1/2)), and C (max) were 7.2 ± 2.3 μg h/mL, 1.2 ± 0.3 h, and 9.2 ± 5.2 μg/mL for cinnamic acid, 53 ± 31 μg h/mL, 2.8 ± 2.0 h, and 17 ± 3 μg/mL for hippuric acid, 1.1 ± 0.5 μg h/mL, 1.9 ± 1.1 h, and 0.6 ± 0.3 μg/mL for paeoniflorin, and 11 ± 6 μg h/mL, 6.6 ± 2.5 h, and 0.9 ± 0.6 μg/mL for glycyrrhetic acid, respectively. The results would offer useful information for effective components of GZD in vivo.
  European Journal of Drug Metabolism and Pharmacokinetics 02/2013;
• Article: Pharmacokinetics, tissue distribution and excretion of manganese (III) meso-tetra [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, a novel superoxide dismutase mimic, in Wistar rats.

  Bao-Qiu Li, Shi-Hong Fang, Xin Dong, Na Li, Ji-You Gao, Gui-Qin Yang, Xian-Chang Gong, Shu-Juan Wang, Feng-Shan Wang
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  ABSTRACT: Manganese (III) 5, 10, 15, 20-tetrakis [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, designated HSJ-0017, is a novel superoxide dismutase mimic. It exhibits strong free-radical scavenging activities in vitro and in vivo. The aim of the present study was to investigate the pharmacokinetics, tissue distribution and excretion of HSJ-0017 in Wistar rats following a single intravenous administration. Wistar rats were given different doses of HSJ-0017 by single intravenous injection. Biological samples of rats were collected and were assayed by the HPLC method. The pharmacokinetics, tissue distribution and excretion of HSJ-0017 were investigated. The pharmacokinetic data of HSJ-0017 in rats following intravenous injection was best-fit by a two-compartment model. T (max) of HSJ-0017 in plasma following intravenous injection was 0.083 h. AUC and plasma drug concentration were found to increase in a dose-related fashion. The highest concentrations of HSJ-0017 were detected in the liver (82.25 ± 13.99 μg/g) of rats, followed by the kidney, small intestine, lung, plasma, heart, spleen, and stomach within 2 h postdose. No HSJ-0017 was detected in the uterus, parorchis or brain of rats during the 24-h period of examination. The total cumulative excretion of HSJ-0017 in rat bile and urine were found to be 78.85 and 67.58 %, respectively. Our study has led to the view that the HSJ-0017 can be rapidly distributed to tissues after intravenous administration, but cannot diffuse through the blood-brain barrier. The faecal and biliary excretion of unchanged HSJ-0017 are the major routes of HSJ-0017 elimination.
  European Journal of Drug Metabolism and Pharmacokinetics 01/2013;
• Article: The impact of drug transporters on adverse drug reaction.

  Yan Zhou, Guo-Qiang Zhang, Yu-Hui Wei, Jian-Ping Zhang, Guo-Rong Zhang, Jiang-Xia Ren, Hao-Gang Duan, Zhi Rao, Xin-An Wu
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  ABSTRACT: In this review, we have highlighted the adverse drug reaction mediated by transporters from two aspects: (1) competitive interactions between drug and drug/metabolite/endogenous substance mediated by transporters; (2) the expression/function change of transporter due to physiologic factors, disease, and drugs induction. It indicated that transporters exhibited a broad substrate specificity with a degree of overlap, which could change the pharmacokinetics of drugs and cause toxicity due to competition interactions among substrates. In addition, the expression and function of transporters were regulated by physiological conditions, pathological conditions, and drugs induction, which could cause adverse drug reaction and interindividual differences. Furthermore, one substrate was always medicated by several transporters and often subjected to metabolism by CYP enzymes, so we should be more aware of the increased plasma concentration of drugs caused by drug transporters as well as drug metabolizing enzymes synergistically, especially for drugs with narrow therapeutic window. In addition, the weightiness for one transporter to induce drugs plasma/tissue concentration change could be different in different condition. On the whole, transporters were corresponding with systemic/organs exposure of drug/metabolites/endogenous compounds. So understanding the expression and function in drug transporters will result in better strategies for optimal dosage regimen and reduce the risk for drug adverse reaction as well as adverse drug-drug interactions.
  European Journal of Drug Metabolism and Pharmacokinetics 01/2013;
• Article: Convolution and validation of in vitro-in vivo correlation of water-insoluble sustained-release drug (domperidone) by first-order pharmacokinetic one-compartmental model fitting equation.

  Anirbandeep Bose, Wong Tin Wui
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  ABSTRACT: The experimental study presents a brief and comprehensive perspective on the methods of developing a Level A in vitro-in vivo correlation (IVIVC) for extended oral dosage forms of water-insoluble drug domperidone. The study also evaluates the validity and predictability of in vitro-in vivo correlation using the convolution technique by one-compartmental first-order kinetic equation. The IVIVC can be substituted as a surrogate for in vivo bioavailability study for the documentation of bioequivalence studies as mandatory from any regulatory authorities. The in vitro drug release studies for different formulations (fast, moderate, slow) were conducted in different dissolution mediums. The f (2) metric (similarity factor) was used to analyze the dissolution data for determination of the most discriminating dissolution method. The in vivo pharmacokinetics parameters of all the formulations were determined by using liquid chromatography mass spectrometry (LC/MS) methods. The absorption rate constant and percentage of absorption of drugs at different time intervals were calculated by using data convolution. In vitro drug release and in vivo absorption correlation were found to be a linear correlation model, which was developed by using percent absorbed drug release versus percent drug dissolved from the three formulations. Internal and external validation was performed to validate the IVIVC. Predicted domperidone concentrations were obtained by convolution technique using first-order one-compartmental fitting equation. Prediction errors estimated for C (max) and AUC (0-infinity) were found to be within the limit.
  European Journal of Drug Metabolism and Pharmacokinetics 12/2012;
• Article: Pharmacokinetics of 5-fluorouracil and increased hepatic dihydropyrimidine dehydrogenase activity levels in 1,2-dimethylhydrazine-induced colorectal cancer model rats.

  Shinji Kobuchi, Yukako Ito, Kae Okada, Kazuki Imoto, Kanji Takada
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  ABSTRACT: To investigate the hepatic dihydropyrimidine dehydrogenase (DPD) activity in colorectal cancer (CRC), which is critically important to create a patient-specific dosing regimen, we performed 5-FU pharmacokinetic studies in 1,2-dimethylhydrazine-induced CRC model rats (CRC rats). After rats received 5-FU intravenous (IV) bolus injections, the area under the plasma concentration-time curve (AUC) and elimination half-life (t (1/2)) in CRC rats (10.02 ± 0.37 μg h mL(-1), 0.30 ± 0.02 h, respectively) were significantly lower than that in control rats (13.46 ± 1.20 μg h mL(-1), 0.52 ± 0.05 h, respectively), whereas total plasma clearance (CL(tot)) in CRC rats (2.01 ± 0.07 L h(-1) kg(-1)) was significantly increased compared with that in control rats (1.54 ± 0.14 L h(-1) kg(-1)). Conversely, the avoidance ratio of the hepatic first-pass effect was approximately 20 % lower than that in control rats. Of interest is that hepatic DPD activity levels and the dihydrouracil-uracil ratio (UH2/Ura ratio) in plasma, which may act as a potential biomarker to evaluate hepatic DPD activity levels, were significantly increased in CRC rats. These results suggest that the decrease of hepatic availability in CRC rats is brought about by the increase in intrinsic clearance induced by the increase in DPD activity, resulting in a decrease in AUC and t (1/2) and an increase in CL(tot) after 5-FU IV bolus injection. Along with a proper dosing regimen for patients with CRC, a hepatic DPD activity monitoring system, such as the determination of UH2/Ura ratio in plasma, is desirable.
  European Journal of Drug Metabolism and Pharmacokinetics 11/2012;
• Article: Genotype and allele frequencies of polymorphic UGT1A9 in the Polish population.

  Oliwia Zakerska, Marzena Skrzypczak-Zielinska, Adam Mikstacki, Barbara Tamowicz, Bianka Malengowska, Marlena Szalata, Ryszard Slomski
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  ABSTRACT: The human UDP-glucuronosyltransferase 1A9 (UGT1A9) plays a central role in the metabolism of different therapeutic drugs, carcinogens and endobiotics. The UGT1A9 gene shows genetic polymorphism with frequencies significantly different in populations and ethnic groups. Many of these genetic variants are directly responsible for polymorphic drug metabolism. Three crucial alleles of UGT1A9, UGT1A9*3 (p.Met33Thr), *4 (p.Tyr242X), *5 (p.Asp256Asn) are associated with decrease or absence of enzyme activity, which intensify the risk of toxic effect during biotransformation. The goal of the present study was to discover frequencies of these genetic variations in 308 healthy individuals representing Polish population. The genotypes were determined by pyrosequencing. We demonstrated that the frequency of the variant UGT1A9*3 was 0.016, which suggests the need for detailed analysis of its effect on important drugs metabolism level in Polish population. Alleles UGT1A9*4 and UGT1A9*5 were not present in any of the subjects. So far, no studies have been conducted in which the distribution of these alleles has been determined in the Polish population.
  European Journal of Drug Metabolism and Pharmacokinetics 11/2012;
• Article: In vivo distribution of 5-Fluorouracil after peritumoral implantation using a biodegradable micro-device in tumor-bearing mice.

  Na Zheng, Mingyao Zhou, Wen Lu
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  ABSTRACT: A novel implantable micro-device was used for delivery of 5-Fluorouracil (5-Fu), which was often used in the treatment of various human malignancies. The biodegradable poly(lactic-co-glycolic) acid (PLGA) was used as material. The purpose of this study was to investigate the efficiency of delivery of 5-Fu to the tumor via this delivery system. The distribution characters of the 5-Fu in tumor, plasma, peritumoral tissue, liver and kidney were compared after peritumoral implantation of micro-device and intraperitoneal injection of solution. After administration of micro-device, the 5-Fu was absorbed into the tumor on Day 1, and Cmax (4.14 μg/g) was reached on Day 6. The half life for the elimination was 4.48 d and the AUC was 46.78 μg × d/g. Similar pharmacokinetic behaviors were observed in plasma, peritumoral tissue, kidney and liver, while the Cmax and the AUC of plasma and these tissues were lower than those of tumor. When administered the solution, 5-Fu was rapidly absorbed into plasma, liver, kidney, spleen and tumor, and rapidly cleared from these tissues after 2 or 4 h. And the AUC in tumor of 5-Fu solution was significantly lower than that of the micro-device. These results indicated that 5-Fu loaded biodegradable micro-device offered a relatively high concentration and long-term delivery of the drug to the tumor site.
  European Journal of Drug Metabolism and Pharmacokinetics 11/2012;