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Effects of Rutaecarpine on the Metabolism and Urinary Excretion of Caffeine in Rats

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Abstract

Although rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, has been reported to reduce the systemic exposure of caffeine, the mechanism of this phenomenon is unclear. We investigated the microsomal enzyme activity using hepatic S-9 fraction and the plasma concentration-time profiles and urinary excretion of caffeine and its major metabolites after an oral administration of caffeine in the presence and absence of rutaecarpine in rats. Following oral administration of 80 mg/kg rutaecarpine for three consecutive days, caffeine (20 mg/kg) was given orally. Plasma and urine were collected serially for up to 24 h and the plasma and urine concentrations of caffeine and its metabolites were measured, and compared with those in control rats. The areas under the curve of both caffeine and its three major metabolites (paraxanthine, theophylline, and theobromine) were significantly reduced by rutaecarpine, indicating that caffeine was rapidly converted into the desmethylated metabolites, and that those were also quickly transformed into further metabolites via the hydroxyl metabolites due to the remarkable induction of CYP1A2 and 2E1. The significant induction of ethoxyresorufin O-deethylase, pentoxyresorufin O-depentylase, and p-nitrophenol hydroxylase strongly supported the decrease in caffeine and its major metabolites in plasma, as well as in urine. These results clearly suggest that rutaecarpine increases the metabolism of caffeine, theophylline, theobromine, and paraxanthine by inducing CYP1A2 and CYP2E1 in rats.

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... To better understand caffeine effects on living organisms, it is necessary to investigate caffeine's pharmacokinetics and pharmacodynamic properties. Several analytical methods using LC coupled to MS/MS (LC-MS/MS) have been reported to determine caffeine or its metabolites in biological samples [8,[15][16][17][18][19][20][21][22][23][24][25][26]. However, some of these methods suffer from disadvantages, such as longer run time [8,16], a relatively large sample volume [19,23] and time-consuming or expensive sample pretreatment [15,17], which reduce sample throughput. ...
... However, some of these methods suffer from disadvantages, such as longer run time [8,16], a relatively large sample volume [19,23] and time-consuming or expensive sample pretreatment [15,17], which reduce sample throughput. Moreover, paraxanthine and theophylline have the same multiple reaction monitoring (MRM) transitions (181.1 > 124.1), and their chromatographic separation seems problematic [22]. As caffeine and its metabolites have very similar structures, separating them and using selective MRM transitions to avoid interferences between analytes is necessary. ...
... Although several analytical LC-MS/MS-based methods have been developed to quantify caffeine in biological samples [8,[15][16][17][18][19][20][21][22][23], not all of them are suitable for the determination of caffeine and its metabolites in small experimental animals such as rodents. The limitations of these studies are large sample volume requirements, inadequate concentration range, laborious sample preparation, and low throughput of analysis. ...
Article
Caffeine is a widely consumed psychostimulant with several mechanisms of action and various positive and negative effects on organisms. Caffeine undergoes extensive hepatic metabolism to form main metabolites such as theobromine, theophylline, paraxanthine and 1,3,7‐trimethyluric acid. However, interspecies diversities have been observed in caffeine metabolism. In the present study, we developed a sensitive and straightforward ultra‐high performance liquid chromatography‐tandem mass spectrometry method to quantify caffeine and its primary metabolites, namely theobromine, theophylline, paraxanthine and 1,3,7‐trimethyluric acid in rat plasma. After extraction of analytes using micro solid‐phase extraction plate, analytes were separated by elution gradient on the Acquity UPLC® HSS T3 (50 × 2.1 mm, 1.8 μm) column over 4 min. The detection was done on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring modes using a positive electrospray ionisation interface. The method was successfully validated according to the European Medicine Agency guideline over a concentration range of 5–1 500 ng/mL for caffeine, 5–1 200 ng/mL for theobromine and 2.5–1 200 ng/mL for theophylline, paraxanthine and 1,3,7‐trimethyluric acid. The developed method was applied to analyse samples from animal experiments focusing on the metabolism and effects of caffeine and caffeine‐containing beverages. This article is protected by copyright. All rights reserved
... Rutaecarpine, a pentacyclic indolopyridoquinazolinone alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa [9], has been reported to reduce the systemic exposure of caffeine, as well as a potent inducer of cytochrome P450 (CYP) (CYP1A2 and CYP2E1) enzymes in rats [10]. It is also known to have vasodilation, anti-thrombosis, analgesic, and antianoxic effects [11]. CYP1A2 plays a critical role in drug metabolism because of its wide tissue distribution and high expression in vivo [12]. ...
... The recommendation is to take two capsules (equivalent to 100 mg rutaecarpine), as needed, to reduce caffeine level. Rutaecarpine has been shown to speed up caffeine elimination in rats, after once a day oral dosing for 3 days [11]. However, there is no scientific data to show how soon a single oral dose of rutaecarpine can promote caffeine elimination in vivo. ...
... In the published paper by Noh. et al., 20 mg/kg caffeine and 80 mg/kg rutaecarpine were administered orally [11]. Therefore, for IV caffeine dosing, 15 mg/kg caffeine was selected to account for the incomplete bioavailability of caffeine. ...
Article
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Rutaecarpine is reported as a potent inducer of CYP1A2 enzyme in rats. There are natural herbal supplements containing rutaecarpine that are designed to enhance the CYP1A2-dependent removal of caffeine from blood so that people can have coffee later in the day without causing sleep interference. This study aimed to determine the minimum amount of time needed from oral rutaecarpine administration until the observed effect of rutaecarpine on caffeine pharmacokinetics (PK) in 15 male Sprague-Dawley rats. PK parameters for caffeine and its metabolites in the control and rutaecarpine groups were calculated using WinNonlin®. Results showed that orally administered rutaecarpine at 100 mg/kg dose as early as 3 h before oral caffeine administration significantly decreased the oral systemic exposure and mean residence time of caffeine and its metabolites due to decreased caffeine bioavailability (by up to 75%) and increased clearance. The systemic exposure of caffeine and its metabolites were also decreased when caffeine was given intravenously, though this effect was less pronounced than when caffeine was given orally. Although plasma level of rutaecarpine was undetectable (less than 10 ng/mL), rutaecarpine still induced hepatic CYP1A2 activity. Results from 7-methoxyresorufin O-demethylation activity, which is specific to CYP1A2, showed that 3 h after one rutaecarpine oral dose, CYP1A2 activity in rat liver tissue was increased by 3- fold. This finding suggested that rutaecarpine effectively induced CYP1A2 activity in the liver.
... It has been well documented that edible coatings applied to food before frying aid in limiting moisture and oil transfer during frying (AL-bErt and MIttAL, 2002). the surface modification by the hydrocolloid coatings can contribute to the reduction of the oil uptake during frying (KIM, 2011). ...
... Also agreed with (ALtUNAKAr et al., 2006;AKDENIZ et al., 2006), who concluded that fried foods coated with batters containing hydroxypropyl methylcellulose, xanthan, or guar gum had reduced oil content. KIM et al. (2011) were also obtained that the use of hydrocolloid as coating films of potato strips reduced the oil content up to 41% compared to control. ...
... In our study we observed that paraxanthine and theophylline are metabolized faster than theobromine. A similar study that investigated the effect of rutaecarpine, which is also a cYP450 inducer, shows an increase of elimination rate of all caffeine metabolites after exposure to this drug (NOH et al., 2011). However, according to our findings, tobacco smoke, which contains cYP450 inducer, such as polycyclic aromatic hydrocarbons, has no such effect on theobromine (table 2). the tobacco smoke related cytochrome induction can serve as an explanation. ...
... It has been well documented that edible coatings applied to food before frying aid in limiting moisture and oil transfer during frying (AL-bErt and MIttAL, 2002). the surface modification by the hydrocolloid coatings can contribute to the reduction of the oil uptake during frying (KIM, 2011). ...
... Also agreed with (ALtUNAKAr et al., 2006;AKDENIZ et al., 2006), who concluded that fried foods coated with batters containing hydroxypropyl methylcellulose, xanthan, or guar gum had reduced oil content. KIM et al. (2011) were also obtained that the use of hydrocolloid as coating films of potato strips reduced the oil content up to 41% compared to control. ...
... In our study we observed that paraxanthine and theophylline are metabolized faster than theobromine. A similar study that investigated the effect of rutaecarpine, which is also a cYP450 inducer, shows an increase of elimination rate of all caffeine metabolites after exposure to this drug (NOH et al., 2011). However, according to our findings, tobacco smoke, which contains cYP450 inducer, such as polycyclic aromatic hydrocarbons, has no such effect on theobromine (table 2). the tobacco smoke related cytochrome induction can serve as an explanation. ...
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This paper discusses the concept of the food community network (FCN) and how consumers and farmers organize credence food transactions. The FCN is based on pooling specific resources and using membership-based contracts to assign decision and property rights. It implies an organization based on a combination of several democratic and communitarian elements, with few market-like and bureaucratic elements. By applying arguments from new institutional economics and organizational science, case studies on community-supported agriculture reported elsewhere were used to describe how FCN governance works. The results indicate a great variety of FCN organizational forms.
... It has been well documented that edible coatings applied to food before frying aid in limiting moisture and oil transfer during frying (AL-bErt and MIttAL, 2002). the surface modification by the hydrocolloid coatings can contribute to the reduction of the oil uptake during frying (KIM, 2011). ...
... Also agreed with (ALtUNAKAr et al., 2006;AKDENIZ et al., 2006), who concluded that fried foods coated with batters containing hydroxypropyl methylcellulose, xanthan, or guar gum had reduced oil content. KIM et al. (2011) were also obtained that the use of hydrocolloid as coating films of potato strips reduced the oil content up to 41% compared to control. ...
... In our study we observed that paraxanthine and theophylline are metabolized faster than theobromine. A similar study that investigated the effect of rutaecarpine, which is also a cYP450 inducer, shows an increase of elimination rate of all caffeine metabolites after exposure to this drug (NOH et al., 2011). However, according to our findings, tobacco smoke, which contains cYP450 inducer, such as polycyclic aromatic hydrocarbons, has no such effect on theobromine (table 2). the tobacco smoke related cytochrome induction can serve as an explanation. ...
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The network of scientific collaboration in viticulture and oenology between the United States and the European Union was studied for the period 1991-2010. A total of 498 articles were published collaboratively during this time. The most collaborative institutions in the US were the University of California Davis and Cornell University (New York), and the most collaborative institutions in the EU were Institut Nationale de la Recherche Agronomique (France), the Italian universities of Milan, Bologna and Udine, and the Spanish University of Barcelona. We note a considerable increase in collaboration in recent years, with the University of California Davis situated in a central position in the network.
... It has been well documented that edible coatings applied to food before frying aid in limiting moisture and oil transfer during frying (AL-bErt and MIttAL, 2002). the surface modification by the hydrocolloid coatings can contribute to the reduction of the oil uptake during frying (KIM, 2011). ...
... Also agreed with (ALtUNAKAr et al., 2006;AKDENIZ et al., 2006), who concluded that fried foods coated with batters containing hydroxypropyl methylcellulose, xanthan, or guar gum had reduced oil content. KIM et al. (2011) were also obtained that the use of hydrocolloid as coating films of potato strips reduced the oil content up to 41% compared to control. ...
... In our study we observed that paraxanthine and theophylline are metabolized faster than theobromine. A similar study that investigated the effect of rutaecarpine, which is also a cYP450 inducer, shows an increase of elimination rate of all caffeine metabolites after exposure to this drug (NOH et al., 2011). However, according to our findings, tobacco smoke, which contains cYP450 inducer, such as polycyclic aromatic hydrocarbons, has no such effect on theobromine (table 2). the tobacco smoke related cytochrome induction can serve as an explanation. ...
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The study aim was to assess the behaviour of Listeria monocytogenes during the production and shelf life of artisan water buffalo mozzarella cheese (WbMc) under different storage conditions. raw milk was deliberately contaminated by L. monocytogenes and the evolution of L. monocytogenes count during production and shelf life was monitored. In traditional WbMc production technology L. monocytogenes can multiply in the curd during ripening, but its growth rate expressed in log CFU/g/h is lower than the growth rate reported by theoretical predictions. Stretching proved to be a process with good repeatability and able to reduce L. monocytogenes contamination by about 2 Log CFU/g. The intrinsic characteristics of traditional WBMC proved to be able to obstacolate the growth of L. monocytogenes during storage even in the case of severe thermal abuse.
... Furthermore, caffeine and its three major metabolites have also been used as a tool for studying drug-drug interactions. For example, we recently reported that rutaecarpine might cause signifi cant changes in oral caffeine pharmacokinetics (Noh et al., 2011). In the study, it was found that caffeine was rapidly converted to its three N-demethylated metabolites, which were also quickly transformed to further metabolites, when animals were pretreated with rutaecarpine, a CYP inducer. ...
... Further metabolism of three demethylated metabolites to others was supported by signifi cant induction of CYP1A2 and CYP2E1 by rutaecarpine (Lee et al., 2004a). Meanwhile, no evidence has been found in the study, regarding possible effects of rutaecarpine on the transporters for caffeine absorption in gastrointestinal tract, and it was postulated that the repeated dose of rutaecarpine might cause the expression of drug transporters in our recent study (Noh et al., 2011). ...
... The AUC last was 10.67 ± 0.92 μg · hr/ml and the t 1/2(β) was 0.42 ± 0.06 hr, which were 21.0% and 17.6% of control, respectively. In our previous study, oral caffeine showed decrease to 5.2% and 37.0% in the AUC and half-life by rutaecarpine pretreatment, respectively (Noh et al., 2011). In addition, MRT last of caffeine signifi cantly decreased to 26.7% of control by rutaecarpine pretreatment. ...
Article
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Rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, has been shown to be anti-inflammatory. In the present study, a possible interaction between rutaecarpine and caffeine was investigated in male Sprague Dawley rats. Twenty four hr after the oral pretreatment with rutaecarpine at 80 mg/kg for three consecutive days, rats were treated intravenously with 10 mg/kg of caffeine. Compared with control rats, the pharmacokinetic parameters of caffeine in rutaecarpine-pretreated rats were significantly changed, possibly due to the rapid metabolism. The production of three metabolites of caffeine (i.e., paraxanthine, theobromine and theophylline) was also significantly changed in rats pretreated with rutaecarpine. The present results suggest that oral rutaecarpine would change the intravenous pharmacokinetic characteristics of caffeine.
... Rutaecarpine is such an example. Rutaecarpine has been shown to increase the metabolism and elimination of caffeine (Tsai et al., 2005; Noh et al., 2011), theophylline (Ueng et al., 2005; Jan et al., 2005), acetaminophen (Lee et al., 2007), and Rhizoma coptidis alkaloids (Ma et al., 2011), indicating that rutaecarpine could act on drug processing genes in the liver, which would include Phase-1 (cytochrome P450), Phase-2 (conjugation reaction), and Phase-3 metabolism (drug transporters). Rutaecarpine treatment is well-known to induce the activity of hepatic cytochrome P450 enzyme/genes in animals, particularly CYP1A1 and 1A2 enzyme genes (Ueng et al., 2001Ueng et al., , 2002aUeng et al., , 2002b Lee et al., 2004; Han et al., 2009), at both protein and activity levels. ...
... Curiously, in liver microsome incubations, rutaecarpine is an inhibitor of CYP1A enzymes when added in vitro (Ueng et al., 2002c). Thus, induction of CYP enzyme has been proposed as a mechanism of rutaecarpine effects on increased metabolism of theophylline (Ueng et al., 2005), acetaminophen (Lee et al., 2007), and caffeine (Noh et al., 2011). Glucuronidation, glutathione conjugation and sulfation conjugation represent the three most prevalent classes of phase-2 metabolism, which may occur directly on the parent compounds that contain appropriate structural motifs, or, as is usually the case, on functional groups added or exposed by phase-1 oxidation (Gliszczynski et al., 2006). ...
... Phase-2 conjugations are an important aspect of herb–drug interactions (Li et al., 2012). The Phase-2 conjugation reactions are important for acetaminophen , caffeine, and theophylline excretion through the bile (Lee et al., 2004; Tsai et al., 2005; Ueng et al., 2005; Noh et al., 2011). Effects of rutaecarpine on cytochrome P450s have been extensively studied; however, its effects on Phase-2 conjugation metabolism have not been adequately investigated. ...
Article
Ethnopharmacological relevance: Rutaecarpine is an alkaloid of Evodia rutaecarpa which is traditionally used to treat human diseases. Rutaecarpine has been used in combination with other drugs in the treatment of disorders and found to produce herb-drug interactions. The basis of these herb-drug interactions is not completely understood. Aim of study: To examine the effects of rutaecarpine on the expression of drug processing genes, including Phase-1 (P450 enzyme genes), Phase-2 (glucuronidation and sulfation genes) and Phase-3 (drug transporters) in liver of mice. Materials and methods: Mice were orally administered rutaecarpine at the doses of 10, 20, and 30 mg/kg for consecutive 7 days. Twenty-four hours after the last dose, blood and liver were collected. Total RNA was isolated, purified, and subjected to real-time RT-PCR analysis of genes of interest. Results: Rutaecarpine administration induced Cyp1a2, 2b10 and 2e1 as previously reported. Cyp3a11 and Cyp4a10 were also induced. For phase-2 enzyme genes, rutaecarpine increased glucuronyltransferases (Ugt1a1 and Ugt1a6), but had no effects on sulfotransferase (Sult1a1 and Sult1b1). Most interestingly, rutaecarpine increased hepatic uptake of organic anion transporting peptides (Oatp1a1, Oayp1a4, Oatp1b2, and Oatp2b1) and induced efflux transporter such as multidrug resistance-associated proteins (Mrp1, Mrp2, Mrp3, and Mrp4), especially at the doses of 20mg/kg and above. Conclusion: The interactions of rutaecarpine with drugs involve not only the induction of cytochrome P450 enzyme genes, but also the induction of hepatic transporters and phase-2 enzyme genes. The effects of rutaecarpine on these drug processing genes could play integrated roles in producing herb-drug interactions.
... AUC was calculated using the trapezoidal rule-extrapolation method (Chiou, 1978). The pharmacokinetic parameters were expressed as mean ± SD obtained from 5 rats (Noh et al., 2011). The statistical significance of the results was analyzed using Student's t-test, with p-values of less than 0.05 considered statistically significant. ...
... Because the microsomes isolated from control rats were not useful to study the effects of test compound on specific CYP isozymes, the rats were pretreated with specific CYP inducers to enrich CYP 1A, 2B, 2E1 and 3A by 3-methylcholanthrene, phenobarbital, acetone, and dexamethasone, respectively (Noh et al., 2011). Baicalin and baicalein showed inhibitory effects on EROD and MROD in vitro, the markers for CYP1A. ...
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Scutellaria baicalensis is one of the most widely used herbal medicines in East Asia. Because baicalein and baicalin are major components of this herb, it is important to understand the effects of these compounds on drug metabolizing enzymes, such as cytochrome P450 (CYP), for evaluating herb-drug interaction. The effects of baicalin and baicalein on activities of ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), benzyloxyresorufin O-debenzylase (BROD), p-nitrophenol hydroxylase and erythromycin N-demethylase were assessed in rat liver microsomes in the present study. In addition, the pharmacokinetics of caffeine and its three metabolites (i.e., paraxanthine, theobromine and theophylline) in baicalin-treated rats were compared with untreated control. As results, EROD, MROD and BROD activities were inhibited by both baicalin and baicalein. However, there were no significant differences in the pharmacokinetic parameters of oral caffeine and its three metabolites between control and baicalin-treated rats. When the plasma concentration of baicalin was determined, the maximum concentration of baicalin was below the estimated IC50 values observed in vitro. In conclusion, baicalin had no effects on the pharmacokinetics of caffeine and its metabolites in vivo, following single oral administration in rats.
... The values of T 1/2 , CL, volume, and area under the curve (AUC) were 29.29 min, 63.46 mL/min kg, 655.15 mL/kg, and 32.93 µg/min·mL, respectively (Ko et al., 1994). Ruteacarpine (7) was reported to induce activities of CYP 1A2, 2E1, and 2B in rats, in addition to pharmacokinetic parameters of several compounds (e.g., acetaminophen and caffeine) (Noh et al., 2011;Sang et al., 2007). The pharmacokinetic parameters of evodiamine (8) in rats were reported by Komatsu et al. (1993). ...
... Plasma concentrations of caffeine and its three metabolites, paraxanthine, theobromine, and theophylline, were determined by the previous reported method with some modifications (Noh et al., 2011;Choi et al., 2013). Caffeine and its metabolites were analyzed using high performance liquid chromatography (1260 system, Agilent) with mass spectrometry (API-4000, AB SCIEX). ...
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Pharmacokinetic interaction of chrysin, a flavone present in honey, propolis and herbs, with caffeine was investigated in male Sprague-Dawley rats. Because chrysin inhibited CYP1A-selective ethoxyresorufin O-deethylase and methoxyresorufin O-demethylase activities in enriched rat liver microsomes, the pharmacokinetics of caffeine, a CYP 1A substrate, was studied following an intragastric administration with 100 mg/kg chrysin. In addition to the oral bioavailability of chrysin, its phase 2 metabolites, chrysin sulfate and chrysin glucuronide, were determined in rat plasma. As results, the pharmacokinetic parameters for caffeine and its three metabolites (i.e., paraxanthine, theobromine and theophylline) were not changed following chrysin treatment in vivo, despite of its inhibitory effect on CYP 1A in vitro. The bioavailability of chrysin was found to be almost zero, because chrysin was rapidly metabolized to its sulfate and glucuronide conjugates in rats. Taken together, it was concluded that the little interaction of chrysin with caffeine might be resulted from the rapid metabolism of chrysin to its phase 2 metabolites which would not have inhibitory effects on CYP enzymes responsible for caffeine metabolism.
... The time-course of a bolus dose showed near total clearance of caffeine and its metabolites in about 12 h as reported in a number of articles (e.g. Choi et al., 2013;Noh et al., 2011Noh et al., , 2015. However, since rats in all groups had access to caffeine ad lib for four weeks we assumed they all have a fairly similar steady level of caffeine. ...
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We have investigated the neuroprotective effect of chronic caffeine treatment on basal levels of memory-related signaling molecules in area CA1 of sleep-deprived rats. Animals in the caffeine groups were treatedwith caffeine in drinking water (0.3 g/l) for four weeks before they were REMsleep-deprived for 24 h in the Modified Multiple Platforms paradigm. Western blot analysis of basal protein levels of plasticity- and memory-related signaling molecules in hippocampal area CA1 showed significant down regulation of the basal levels of phosphorylatedand total-CaMKII, phosphorylated- and total-CREB as well as those of BDNF and CaMKIV in sleep deprived rats. All these changes were completely prevented in rats that chronically consumed caffeine. The present findings suggest an important neuroprotective property of caffeine in sleep deprivation.
... In our study we observed that paraxanthine and theophylline are metabolized faster than theobromine. A similar study that investigated the effect of rutaecarpine, which is also a cYP450 inducer, shows an increase of elimination rate of all caffeine metabolites after exposure to this drug (NOH et al., 2011). However, according to our findings, tobacco smoke, which contains cYP450 inducer, such as polycyclic aromatic hydrocarbons, has no such effect on theobromine (table 2). the tobacco smoke related cytochrome induction can serve as an explanation. ...
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Caffeine and nicotine are some of the most often self-administered substances worldwide. Very often they are taken simultaneously and it seems that this fact is correlated with the amount of caffeine and nicotine administered. The aim of this study is to determine, whether tobacco smoke influences the metabolism of caffeine. The secondary task is to establish whether caffeine has an effect on elimination of cotinine, nicotine’s main metabolite. The results showed that tobacco smoke influences the metabolism of caffeine by accelerating its elimination, by the means of induced CYP1A2 activity. As far as cotinine is concerned, no influence of caffeine on its elimination was observed.
... Concomitantly, Zhu et al. [65] reported that rutaecarpine, an alkaloid found in Evodia rutaecarpa traditionally used in combination with Chinese traditional medicine, had profound effects on the hepatic drug processing enzyme gene expression, CYP enzyme genes and UDP-glucuronosyltransferase, and increased the expression of hepatic uptake and efflux transporters. The authors speculated that all these effects could play an integrated role in rutaecarpine-increased metabolism and elimination of caffeine [66], theophylline [67], and acetaminophen [68]. ...
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Various reports suggest a high contemporaneous prevalence of herb-drug use in both developed and developing countries. The World Health Organisation indicates that 80% of the Asian and African populations rely on traditional medicine as the primary method for their health care needs. Since time immemorial and despite the beneficial and traditional roles of herbs in different communities, the toxicity and herb-drug interactions that emanate from this practice have led to severe adverse effects and fatalities. As a result of the perception that herbal medicinal products have low risk, consumers usually disregard any association between their use and any adverse reactions hence leading to underreporting of adverse reactions. This is particularly common in developing countries and has led to a paucity of scientific data regarding the toxicity and interactions of locally used traditional herbal medicine. Other factors like general lack of compositional and toxicological information of herbs and poor quality of adverse reaction case reports present hurdles which are highly underestimated by the population in the developing world. This review paper addresses these toxicological challenges and calls for natural health product regulations as well as for protocols and guidance documents on safety and toxicity testing of herbal medicinal products.
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Introduction: Euodiae fructus, also known as Evodiae fructus, is a popular Chinese herbal medicine derived from the dried, nearly ripe fruits of Tetradium ruticarpum (A. Juss.) T. G. Hartley. The main bioactive constituents of Euodiae fructus are alkaloids, limonoids, flavonoids, and anthraquinones. The contents of these compounds vary greatly between different plant species, geographic locations, and harvest times, which thus affect the therapeutic effects. Objectives: We aimed to summarize the chromatographic and mass spectrometric technologies applied for chemical analysis and quality evaluation of Euodiae fructus. Moreover, we aimed to emphasize the diverse soft ionization techniques and mass analyzers of LC-MS methods for assessment of Euodiae fructus. Methodology: A literature study was carried out by retrieving articles published between January 1988 and December 2021 from well-known databases, including PubMed, ASC, Elsevier, ScienceDirect, J·STAGE, Thieme, Taylor & Francis, Springer Link, Wiley Online Library, and CNKI. The chemical analysis methods were described in several categories in accordance with the used analytical techniques, including thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), high-performance liquid chromatography-mass spectrometry (HPLC-MS), gas chromatography-mass spectrometry (GC-MS), capillary electrophoresis (CE), and counter-current chromatography (CCC). Results: This review systematically summarizes the achievements in chemical analysis and quality evaluation of Euodiae fructus published in over three decades, covering the various chromatographic and mass spectrometric technologies applied for identification and quantification of phytochemical constituents. Conclusion: The summary serves as an important basis for future phytochemical research and implementation of quality control methods in order to ensure the efficacy and safety of Euodiae fructus.
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Background: Liver is the pivotal organ responsible for plasma protein production, biliary secretion, xenobiotic elimination, glucose and lipid homeostasis. Dysregulation of these functions usually leads to liver diseases and further related complications. The incidence of liver diseases is increasing worldwide, with high morbidity and mortality when at advanced stages, and has become significant public health concern and substential economic burden. Thus, novel therapeutic strategies for managing liver diseases progression are urgently required. T. ruticarpum is one of the most famous and frequently used herbal medicine and has been prescribed in traditional Chinese medicine (TCM) formulas for the treatment of various ailments, including liver diseases. A considerable amount of bioactive ingredients have been isolated and identified from the roots of T. ruticarpum, including alkaloids, saponins, phenols, volatile oils and other compounds. Among these compounds, evodiamine (EVO) and rutaecarpine (RUT) are believed to be the most bioactive compounds. Purpose: To summarize recent findings regarding to the metabolism, pharmacological/toxicological effects of EVO and RUT and to highlight the potential therapeutic effects of them against liver diseases. Methods: Online academic databases (including PubMed, Google Scholar, Web of Science and CNKI) were searched using search terms of "T. ruticarpum", "Wu Zhu Yu", "evodiamine", "rutaecarpine", "liver" and combinations to include published studies of EVO and RUT primarily from 2004-2019. Several critical previous studies beyond this period were also included. Results: Evodiamine (EVO) and rutaecarpine (RUT) are believed to be the most bioactive alkaloids in T. ruticarpum, having anti-inflammation, anti-fibrosis, anti-lipotoxicity, anti-cancer activities, and thus having potential to improve liver disorders. In the current review, we comprehensively summarized recent progresses in the studies of EVO- and RUT-mediated promising hepatoprotective effects and also provide novel insights regarding the potential use of EVO and RUT as therapeutic options for the treatment of liver diseases. Conclusion: With further in-depth pharmacology and pharmacokinetic studies, we believe that natural products in T. ruticarpum and their derivatives will become promising medicines with improved clinical efficacy for the treatment of liver diseases in the immediate future.
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1. Rutaecarpine, a quinolone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, is one of the main active components used in a variety of clinical applications, including the treatment of hypertension and arrhythmia. However, its hepatotoxicity has also been reported in recent years. 2. Reactive metabolites (RMs) play a vital role in drug-induced liver injury. Rutaecarpine has a secondary amine structure that may be activated to RMs. The aim of the study was to investigate the inhibition of rutaecarpine on CYPs and explore the possible relationship between RMs and potential hepatotoxicity. 3. A cell counting kit-8 cytotoxicity assay indicated that rutaecarpine can decrease the primary rat hepatocyte viability, increase lactate dehydrogenase and reactive oxygen species, reduce JC-1, and cause cell stress and membrane damage. The indexes were significantly restored by adding ABT, an inhibitor of CYPs. A cocktail assay showed that CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 can be inhibited by rutaecarpine in human liver microsomes. The IC50 values of CYP1A2 with and without NADPH were 2.2 and 7.4 μM, respectively, which presented a 3.3 shift. The results from a metabolic assay indicated that three mono-hydroxylated metabolites and two di-hydroxylated metabolites were identified and two GSH conjugates were also trapped. 4. Rutaecarpine can inhibit the activities of CYPs and exhibit a potential mechanism-based inhibition on CYP1A2. RMs may cause herb–drug interactions, providing important information for predicting drug-induced hepatotoxicity.
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A simple method to synthesize N-heteropolycyclic quinazolinones was developed including Knoevenagel condensation of quinazolines and aldehydes and Friedel-Craft alkylation as key steps. Knoevenagel reaction of 2-methyl-3-phenylquinazolin-4(3H)-one proceeded smoothly under a basic condition and subsequent Friedel-Craft alkylation with Brønsted acid gave the N-heteropolycyclic quinazolinones in good yields. Furthermore, these new polycyclic compounds were converted into organic molecules having a long π-conjugation system by treatment of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to utilize them as organic dyes.
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When livestock are poisoned by plants in a range setting, there is normally more than one poisonous plant in that area. Additionally, many plants contain more than one compound that is toxic to livestock. Frequently, much is known regarding the toxicity of the individual plants and their individual toxins; however, little is known regarding the effect of co-exposure to multiple toxic plants or even the effect of multiple toxins from an individual plant. In this review, we discuss some basic principles of mixture toxicology with a focus on our recent research wherein we examined the effect of co-administering multiple plant toxins from the same plant and the effect of co-administration of two different poisonous plants, each with different types of toxins. As combined intoxications are likely common, this information will be useful in further developing management recommendations for ranchers, and in designing additional experiments to study the toxicity of multiple poisonous plants to livestock.
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A rapid, sensitive, simple and accurate LC-MS/MS method for the simultaneous quantitation of caffeine, and its three primary metabolites, theobromine, paraxanthine, and theophylline, in rat plasma was developed and validated. Chromatographic separation was performed on an Agilent Poroshell 120 EC-C18 column using 1μg/mL acetaminophen as an internal standard. Each sample was run at 0.5mL/min for a total run time of 7min/sample. Detection and quantification were performed using a mass spectrometer in selected reaction-monitoring mode with positive electrospray ionization. The lower limit of quantification was 5ng/mL for all analytes with linear ranges up to 5000ng/mL for caffeine and 1000ng/mL for its metabolites. The coefficient of variation for assay precision was less than 12.6%, with an accuracy of 93.5-114%. The assay was successfully applied to determine plasma concentrations of caffeine, theobromine, paraxanthine, and theophylline in rat administered various energy drinks containing the same caffeine content. Various energy drinks exhibited considerable variability in the pharmacokinetic profiles of caffeine and its three primary metabolites, even containing the same caffeine. Different additives of energy drinks might contribute to these results.
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The compound herbal medicine Wu-chu-yu-tang is used for the treatment of migraine and vomiting accompanying a cold. To assess the interactions of herb and drug metabolism, effects of Wu-chu-yu-tang on hepatic and renal cytochrome P450 (CYP), UDP-glucuronosyl transferase (UGT) and glutathione S-transferase (GST) were studied in C57BL/6J mice. Treatment of mice with 5 g/kg per day Wu-chu-yu-tang for 3 days caused 2.5-fold and 2.9-fold increases of liver microsomal 7-ethoxyresorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation activities, respectively. However, CYP activities toward 7-ethoxycoumarin, benzphetamine, N-nitrosodimethylamine, erythromycin and nifedipine, and conjugation activities of UGT and GST were not affected. In kidney, Wu-chu-yu-tang-treatment had no effects on Cyp, UGT and GST activities. Among the four component herbs of Wu-chu-yu-tang, only Evodiae Fructus (Wu-chu-yu) extract increased EROD activity and CYP1a2 protein level. In E. Fructus, rutaecarpine, evodiamine and dehydroevodiamine are the main active alkaloids. At the doses corresponding to their contents in Wu-chu-yu-tang, rutaecarpine-treatment increased hepatic EROD activity, whereas evodiamine and dehydroevodiamine had no effects. These results demonstrated that ingestion of Wu-chu-yu-tang elevated mouse hepatic Cyp1a2 activity and protein level. E. Fructus and rutaecarpine contributed at least in part to the CYP1a2 induction by Wu-chu-yu-tang. Patients should be cautioned about the drug interaction of Wu-chu-yu-tang and CYP1A2 substrates.
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Rutaecarpine is a main active alkaloid present in the medicinal herb, Evodia rutaecarpa. The cytochrome P450 (CYP) 1A2 substrate, theophylline, is an important therapeutic agent for the treatment of asthma, but has a narrow therapeutic index. To evaluate the pharmacokinetic interaction of theophylline with rutaecarpine, the effects of rutaecarpine on CYP1A2 activity and theophylline pharmacokinetics were investigated. Oral treatment of Sprague-Dawley rats with 50 mg kg(-1) rutaecarpine for three days through a gastrogavage caused a 4- and 3-fold increase in liver microsomal 7-ethoxyresorufin O-deethylation (EROD) and 7-methoxyresorufin O-demethylation activity, respectively. In the kidney, rutaecarpine treatment caused a 3-fold increase in EROD activity. In the lungs, EROD activity was elevated from an undetectable to a detectable level by rutaecarpine. Pharmacokinetic parameters of theophylline were determined using a microdialysis sampling method. Rutaecarpine pre-treatment increased the clearance of theophylline in a dose-dependent manner. Pre-treatment of rats with 50 mg kg(-1) rutaecarpine caused a 3-fold increase in theophylline clearance and a 70%, 68% and 68% decrease in the area under the concentration-time curve (AUC), mean residence time (MRT) and half-life, respectively. These results demonstrated that rutaecarpine treatment elevated CYP1A2 catalytic activity and theophylline excretion in rats. In patients taking theophylline, adverse effects might be noticed when a rutaecarpine-containing herbal preparation is used concomitantly.
Article
It has been reported that hepatic microsomal cytochrome P450(CYP) 2E1 is responsible for the metabolism of chlorzoxazone(CZX) to 6-hydroxychlorzoxazone. The present study was undertaken to assess the possible interaction of rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, with CZX. Male Spraque-Dawley rats were administered with 80 mg/kg/day of oral rutaecarpine for three consecutive days. Twenty four hr after the pre-treatment with rutaecarpine, the rats were treated with 20 mg/kg of intravenous CZX. Rat hepatic microsomes isolated from rutaecarpine-treated rats showed greater(50% increase) activity of p-nitrophenol hydroxylase(a marker of CYP2E1) when compared with the control rats. Compared with control rats, the AUC of CZX was significantly smaller(84% decrease) possibly due to significantly faster CL(646% increase) in rats pretreated with rutaecarpine. This could be, at least partially, due to induction of CYP2E1 by rutaecarpine.
Article
Indoloquinazoline alkaloid rutaecarpine was efficiently synthesized by employing 9,10,11,12-tetrahydro-4H-pyrido[2,1-b]quinazoline-4,9-dione as a key intermediate, whose 9-carbonyl group was introduced by benzylidene formation, followed by ozonolysis.
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Population and family studies were undertaken to validate caffeine as a probe drug to establish the genetic status of rapid acetylators and slow acetylators. The acetylator status was established from the urinary metabolic ratio of 5-acetylamino-6-formylamino-3-methyluracil to 1-methylxanthine (AFMU/1X) after oral administration of caffeine. We confirmed a bimodal distribution (X21 = 229.48; p « 10 -9) of the AFMU/1X ratio in 245 unrelated subjects. A third distribution did not significantly improve the fit to the data (X21 0.04; p = 0.84). Complex segregation analysis of 76 nuclear families confirmed the monogenic inheritance of N-acetyltransferase, with incomplete dominance of the rapid allele over the slow one. We observed a slight shift between the mean activities of heterozygous and homozygous rapid acetylators (t = 2.89; p < 0.01). However, the 30 obligate heterozygotes belonging to the 76 families were evenly distributed among the rapid acetylators and never located in a hypothetic intermediary group between slow acetylators and rapid acetylators.
The linear trapezoidal rule method is commonly used for the estimation of the area under the plasma level-time curve. Error analyses are performed when the method is used in first-order absorption and first-order elimination kinetics in the one-compartment system. It is found that significant underestimations and overestimations in area during the absorption phase and postabsorption phase, respectively, can occur when the method is improperly used. During the exponential postabsorption phase the relative error is only a function of the ratio (n) of the time interval over the half-life of the two plasma data points in the interval. The error from the linear trapezoidal rule method at n = 0.5 is about 1%. The error increases to 15.5% and 57.1% when n is increased to 2 and 4, respectively. It is recommended that for most absorption studies the linear trapezoidal method be used for prepeak and plateau plasma data and the logarithmic trapezoidal method for postpeak plasma data.
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Suppression of murine humoral immunity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to occur in vivo and in vitro. Studies have indicated that suppression of humoral immunity is mediated by the Ah receptor. Data presented in this paper demonstrate that alpha-naphthoflavone (ANF) and beta-naphthoflavone (BNF), like TCDD, bind to rat and murine hepatic and murine splenocyte cytosolic Ah receptor. Furthermore, BNF induces cytochrome P1-450 monooxygenase activity as measured by ethoxyresorufin-O-deethylase (EROD) in murine spleen cells to the same extent as TCDD. In contrast, ANF predominantly acts to antagonize TCDD induction of splenocyte EROD activity. Examination of humoral immunity in vitro demonstrated that BNF, like TCDD, is suppressive. Whereas ANF is suppressive at cytotoxic concentrations, lower concentrations of ANF antagonize the suppressive effect of TCDD. Antagonism by ANF of TCDD-induced EROD activity and suppression of humoral immunity occur at similar concentrations. These data suggest that ANF blocks TCDD suppression of B lymphocyte differentiation by competing with TCDD for binding to the Ah receptor. Since the mechanism of TCDD toxicity is not fully understood, probes such as ANF may be of great use in examining the role of the Ah receptor in mediating toxicity.
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The hydroxylation of p-nitrophenol to 4-nitrocatechol was investigated using rabbit hepatic microsomes and six purified isozymes of cytochrome P-450. The microsomal activity was maximal at pH 6.8 and at 100 microM p-nitrophenol. At higher substrate concentrations inhibition was observed. At pH 6.8 and 100 microM p-nitrophenol, isozyme 3a exhibited the highest activity of the purified isozymes: 3.4-fold more active than isozyme 6, and 8-fold more active than isozymes 2 and 4. The isozyme 3a-catalyzed hydroxylation reaction was stimulated 2.4-fold by the addition of a 4:1 ratio of cytochrome b5/P-450. At optimal concentrations of cytochrome b5, isozyme 3a was 8- to 9-fold more active than isozymes 2 and 6 and 20-fold more active than isozyme 4. Under the same conditions, isozyme 3a-catalyzed butanol oxidation was inhibited 40%. Antibodies to isozyme 3a inhibited greater than 95% of the p-nitrophenol hydroxylase activity of microsomes from untreated or from ethanol- or acetone-treated rabbits. The microsomal hydroxylase activity was linearly correlated with the microsomal concentration of isozyme 3a (correlation coefficient of 0.94) and had an intercept near zero. The results from reconstitution, antibody inhibition, and correlation experiments indicate that isozyme 3a is the principal catalyst of rabbit microsomal p-nitrophenol hydroxylation. The ability of the ethanol-inducible isozyme to catalyze catechol formation may be important in the ethanol-enhanced toxicity of aromatic compounds such as benzene.
Article
The O-dealkylation of pentoxyresorufin (7-pentoxyphenoxazone) by rat liver microsomes was examined. The reaction appeared highly specific for certain phenobarbital inducible forms of cytochrome P-450 and was increased 95- to 140-fold by animal pretreatment with phenobarbital (75 mg/kg/day, four ip injections) and approximately 50-fold by Aroclor 1254 (500 mg/kg, one ip injection) while animal pretreatment with 3-methylcholanthrene (50 mg/kg/day, three ip injections) resulted in less than a 2-fold increase over the rate detected in control microsomes. It was observed that this activity, in microsomes for Aroclor-pretreated rats, was dependent on O2 and was inhibited by metyrapone and SKF 525-A, indicative of cytochrome(s) P-450 mediation in the reaction. When antibodies directed against purified cytochrome(s) P-450s were employed to inhibit the pentoxyresorufin O-dealkylation reaction, antibodies to P-450PB-B greatly inhibited the reaction (greater than 90%), while antibodies to P-450PB-C or P-450PB/PCN-E had minimal effects. Assay of hepatic microsomes from rats which were pretreated with varying doses of phenobarbital (0.9-75 mg/kg/day, four ip injections) indicated that while aminopyrine-N-demethylase activity was induced only 2-fold at the maximum dose (75 mg/kg/day), pentoxyresorufin O-dealkylase activity was induced approximately 140-fold at this dose and approximately 4-fold by a dose of phenobarbital as low as 0.9 mg/kg.
Article
The vasoreactivity of dehydroevodiamine (1), evodiamine (2), and rutaecarpine (3), quinazoline alkaloids isolated from Evodia rutaecarpa, to aorta smooth muscle demonstrated that they produce a vasodilatory effect on endothelium-intact rat aorta with equal potency. Compound 3 produced a full (100%) nitric oxide-dependent vasodilatation, whereas 2 and 1 produced a partially endothelium-dependent effect, 50% and 10%, respectively. At the same time, I and 2 may also act by other mechanisms, including probably an alpha1-adrenoceptor blocking action and a 5-HT antagonizing action, respectively.
Article
Previous reports indicated that treatment of rats with green tea or black tea extracts increased CYP1A2 activity, but such an induction was not observed with decaffeinated green tea in our preliminary study. Herein we report a comparative study on the induction of CYP1A2 with different tea preparations and caffeine as an inducer. When green tea (2%) or black tea (2%) was given to male Fischer 344 rats as the sole source of drinking fluid for 21 days, a 2.4- or 2.7-fold induction, respectively, of CYP1A2-dependent O-methoxyresorufin demethylase (MROD) activity in liver microsomes was observed. Treating rats with caffeine (0.04%) also resulted in an 1.9-fold increase in the MROD activity, but decaffeinated green tea (0.8%) did not cause such an induction. Rats treated with green tea (2%) or caffeine (0.055%) as the sole source of drinking fluid for 1, 3, and 7 days also showed comparable induction (from 1.7- to 2.1-fold) of the MROD activity. The induction was also shown by intragastric administration of caffeine (100 mg/kg). The induced MROD activity caused by consumption of green tea, black tea, and caffeine corresponded to the increase in liver microsomal CYP1A2 protein, as determined by immunoblot analysis. The concentrations of tea polyphenols and caffeine in plasma were also measured. Close correlation of the increase in the MROD activity was observed only with the plasma caffeine level (r = 0.736, n = 10, p = 0.015), not with the combined tea polyphenol level (r = 0.058, n = 6, p = 0.913). The present study establishes caffeine as an inducer of CYP1A2 and demonstrates that caffeine, not tea polyphenols, is the component in tea responsible for the induction of this enzyme.
Article
We investigated the effect of a new class of COX-2 inhibitor, rutaecarpine, on the production of PGD2 in bone marrow derived mast cells (BMMC) and PGE2 in COX-2 transfected HEK293 cells. Inflammation was induced by lambda-carrageenan in male Splague-Dawley (SD) rats. Rutaecarpine (8,13-Dihydroindolo[2',3':3,4]pyridol[2,1-b]quinazolin -5(7H)-one) was isolated from the fruits of Evodia rutaecarpa. BMMC were cultured with WEHI-3 conditioned medium. c-Kit ligand and IL-10 were obtained by their expression in baculovirus. The generation of PGD2 and PGE2 were determined by their assay kit. COX-1 and COX-2 protein and mRNA expression was determined by BMMC in the presence of KL, LPS and IL-10. Rutaecarpine and indomethacin dissolved in 0.1% carboxymethyl cellulose was administered intraperitoneally and, 1 h later, lambda-carrageenan solution was injected to right hind paw of rats. Paw volumes were measured using plethysmometer 5 h after lambda-carrageenan injection. Rutaecarpine inhibited COX-2 and COX-1 dependent phases of PGD2 generation in BMMC in a concentration-dependent manner with an IC50 of 0.28 microM and 8.7 microM, respectively. It inhibited COX-2-dependent conversion of exogenous arachidonic acid to PGE2 in a dose-dependent manner by the COX-2-transfected HEK293 cells. However, rutaecarpine inhibited neither PLA2 and COX-1 activity nor COX-2 protein and mRNA expression up to the concentration of 30 microM in BMMC, indicating that rutaecarpine directly inhibited COX-2 activity. Furthermore, rutaecarpine showed in vivo anti-inflammatory activity on rat lambda-carrageenan induced paw edema by intraperitoneal administration. Anti-inflammatory activity of Evodia rutaecarpa could be attributed at least in part by inhibition of COS-2.
Article
In order to delineate the mechanism involved in the anti-inflammatory activity of rutaecarpine, its effects on the production of prostaglandin (PG) and therein involved enzymes were examined. Rutaecarpine reduced the production of PGE(2) in RAW264.7 cells treated with lipopolysaccharide (LPS) in a dose dependent manner when added to the culture media at the time of stimulation. However, the inhibition of total cellular cyclooxygenase (COX) activity under the same experimental condition was observed only at high concentrations of rutaecarpine. Rutaecarpine did not affected the levels of COX-2 mRNA and protein in macrophages stimulated with LPS. Calcium ionophore A23187 induced-PG production and [(3)H]-arachidonic acid release were significantly decreased by the pretreatment of rutaecarpine for 30 minutes. With the same treatment schedule, however, rutaecarpine failed to alter the activities of cellular COX-1 and COX-2. Collectively, our data suggest that anti-inflammatory effect of rutaecarpine is, at least in part, ascribed to the diminution of PG production through inhibition of arachidonic acid release albeit the nature of its effects on PLA(2) activity remains to be elaborated.
Article
Rutaecarpine is one of the main alkaloids of an herbal remedy, Evodia rutaecarpa, which has been used for the treatment of gastrointestinal disorder and headache. Effects of rutaecarpine on hepatic and renal cytochrome P450 (CYP)-dependent monooxygenase were studied in C57BL/6J mice. Treatment of mice with rutaecarpine by gastrogavage at 50 mg/kg/day for three days resulted in 57%, 41%, 6-, and 6-fold increases of hepatic microsomal benzo(a)pyrene hydroxylation, 7-ethoxycoumarin O-deethylation, 7-ethoxyresorufin O-deethylation, and 7-methoxyresorufin O-demethylation activities, respectively. However, the treatment had no effects on hepatic oxidation activities toward benzphetamine, N-nitrosodimethylamine, nifedipine, and erythromycin. In the kidney, rutaecarpine-treatment resulted in 2-fold and 42% increases of microsomal benzo(a)pyrene hydroxylation and 7-ethoxycoumarin O-deethylation activities, respectively. The treatment also increased renal 7-ethoxyresorufin O-deethylation activity to a detectable level. Immunoblot analysis of microsomal proteins showed that rutaecarpine-treatment increased the protein levels of CYP1A1 and CYP1A2 in the liver, whereas hepatic level of CYP3A-immunoreacted protein was not affected by rutaecarpine. These CYPs were not detectable in the immunoblot analyses of control and rutaecarpine-treated mouse kidney microsomes. These results indicated that rutaecarpine was a CYP1A inducer and showed potent inductive effects on both CYP1A1 and CYP1A2 in the liver.
Article
Following incubation of rutaecarpine, a new cyclooxygenase-2 inhibitor, with rat liver microsomes, the structures of the metabolites were characterized by liquid chromatography with tandem mass spectrometry. Nine metabolites corresponding to mono- or dihydroxylated rutaecarpine were formed. Characteristic product ions for the identification of rutaecarpine metabolites were observed at m/z 136, 158 and 286. The loss of water led to the fragment ion at m/z 286, indicating the hydroxylation of the aliphatic ring. The fragment ion at m/z 136 indicated the hydroxylated form of the phenyl group of the quinazolinone moiety, while that at m/z 158 indicated the hydroxylated form of the aromatic ring of the indole moiety.
Article
Rutaecarpine is an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa. Recently, rutaecarpine has been characterized to have an anti-inflammatory activity through cyclooxygenase-2 inhibition. In the present studies, the effects of rutaecarpine on liver cytochrome P450 s (P450s) and P450 s involved in the metabolism of rutaecarpine were studied in vivo and in vitro, respectively, because the data are crucial in the early development of rutaecarpine as a new drug candidate. Oral administration to male ICR mice of rutaecarpine for 3 consecutive days induced liver P450 1A-, 2B- and 2E1-selective monooxygenase activities. The induction of P450 1A and 2B by rutaecarpine was confirmed by Western immunoblotting. When rutaecarpine was incubated with rat liver microsomes in the presence of an NADPH-generating system, five metabolites were detected by UV and mass spectral analyses. The 3-methylcholanthrene- and phenobarbital-induced microsomes greatly increased the formation of metabolites. Our present results suggest that rutaecarpine might induce P450 1A and 2B in mice, and that P450 1A and 2B might predominantly metabolize rutaecarpine in rat liver microsomes.
Article
A method using liquid chromatography coupled with mass spectrometry with an atmospheric pressure electrospray source was developed for analysis of labelled caffeine and fourteen of its metabolites in urine. Caffeine metabolic ratios were determined after an oral bolus of labelled caffeine in 20 healthy subjects with different characteristic CYP1A2 activity, relative to smoking habit and oral contraceptive intake. The use of labelled caffeine for the calculation of metabolic ratios avoided taking into account the important background of endogenous caffeine metabolites, very difficult to eliminate even after a specific diet. The selectivity and high sensitivity of mass spectrometry detection allowed urine collections for only a 3h period. Comparison between characteristic groups showed that labelled caffeine metabolic ratios were sensitive markers of changes in CYP1A2 activity.
Article
Pharmaceutical industry investigators routinely evaluate the potential for a new drug to modify cytochrome p450 (p450) activities by determining the effect of the drug on in vitro probe reactions that represent activity of specific p450 enzymes. The in vitro findings obtained with one probe substrate are usually extrapolated to the compound's potential to affect all substrates of the same enzyme. Due to this practice, it is important to use the right probe substrate and to conduct the experiment under optimal conditions. Surveys conducted by reviewers in CDER indicated that the most common in vitro probe reactions used by industry investigators include the following: phenacetin O-deethylation for CYP1A2, coumarin 7-hydroxylation for CYP2A6, 7-ethoxy-4-trifluoromethyl coumarin O-dealkylation for CYP2B6, tolbutamide 4'-hydroxylation for CYP2C9, S-mephenytoin 4-hydroxylation for CYP2C19, bufuralol 1'-hydroxylation for CYP2D6, chlorzoxazone 6-hydroxylation for CYP2E1, and testosterone 6 beta-hydroxylation for CYP3A4. We reviewed the validation information in the literature on these reactions and other frequently used reactions, including caffeine N3-demethylation for CYP1A2, S-mephenytoin N-demethylation for CYP2B6, S-warfarin 7'-hydroxylation for CYP2C9, dextromethorphan O-demethylation for CYP2D6, and midazolam 1'-hydroxylation for CYP3A4. The available information indicates that we need to continue the search for better probe substrates for some enzymes. For CYP3A4-based drug interactions it may be necessary to evaluate two or more probe substrates. In many cases, the probe reaction represents a particular enzyme activity only under specific experimental conditions. Investigators must consider appropriateness of probe substrates and experimental conditions when conducting in vitro drug interaction studies and when extrapolating the results to in vivo situations.
Article
To assess possible herb-drug interactions, rutaecarpine (an herbal ingredient of Evodia rutaecarpa; 25 mg/kg/day, p. o.), the ethanol extract of Evodia rutaecarpa (1 g/kg/day, p. o.), and an herbal preparation of Evodia rutaecarpa (Wu-Chu-Yu-Tang; 1 g/kg/day) were individually pretreated daily for three consecutive days in rats and on the fourth day caffeine was administered (2 mg/kg, i. v.). Caffeine concentrations in blood, brain and bile were concurrently measured by microdialysis coupled to a liquid chromatographic system. Pharmacokinetic data were calculated by a non-compartmental model. The results indicate that the caffeine crosses the blood-brain barrier and goes through hepatobiliary excretion. The caffeine level was significantly decreased by the pretreatment of rutaecarpine, the extract of Evodia rutaecarpa and herbal preparation Wu-Chu-Yu-Tang. This finding should be very important whenever herb-drug interactions would be possible for a herbal remedy.
Article
The extract of Evodia rutaecarpa fruit and its preparation were used for the treatment of gastrointestinal disorders and headache. To assess the possible herb-drug interaction, the ethanol extract of Evodia rutaecarpa fruit (1 and 2 g/kg/day, p.o.) and the herbal preparation Wu-Chu-Yu-Tang (1 and 5 g/kg/day) were given to rats daily for three consecutive days and on the fourth day theophylline was administered (2 mg/kg, i.v.). Theophylline concentration in blood was measured by a microdialysis coupled to a liquid chromatographic system. Pharmacokinetic data were calculated by noncompartmental model. The results indicate that the theophylline level was significantly decreased by the pretreatment with the extract of Evodia rutaecarpa and herbal preparation Wu-Chu-Yu-Tang with dose-related manner. It is suggested that the herb-drug interaction may occur through the induction of the metabolism of theophylline.
Article
From the authors' previous studies on the Phase I metabolism of rutaecarpine, nine metabolites formed were identified as products of hydroxylation on the aromatic rings in rat liver microsomes. In order to determine the possible metabolic fate of rutaecarpine, the Phase II metabolites of rutaecarpine were characterized in the present study by using liquid chromatography/electrospray ionization-tandem mass spectrometry (LC/ESI-MS). When male Sprague-Dawley rats were treated intravenously with 4 mg kg(-1) rutaecarpine, 16 different Phase I and II metabolites were identified in urine including four sulfate and four glucuronide conjugates. Phase I metabolites of rutaecarpine were identified as four mono-hydroxylated metabolites (M2-5) and four isobaric di-hydroxylated metabolites (M6-9). These metabolites were identical to the in vitro metabolites except one, which was hydroxylated in the aliphatic moiety. In addition, Phase II metabolites were identified as conjugated with sulfate (S1-4) and glucuronide (G1-4). In faeces, 11 different metabolites were identified. The metabolites M8 and glucuronide conjugated (G1-4) were not detected. Structures of all metabolites were confirmed with CID fragmentation spectra of MS(2), MS(3) and retention times by LC/ESI-MS.
Article
Rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, has been shown to be anti-inflammatory as it inhibits cyclooxygenase-2. It induces the activities of hepatic CYP 1A2, 2B, and 2E1 in rats. A possible interaction between rutaecarpine and acetaminophen (APAP) was investigated in male Sprague Dawley rats in the present study. When 25 mg/kg APAP was intravenously administered concurrently with 80 mg/kg rutaecarpine, the area under the curve of APAP in plasma was significantly decreased when compared to that of APAP alone. When the rats were pre-treated orally with 40 and 80 mg/kg rutaecarpine for 3 days, the % value of C(max) and area under the curve of acetaminophen-sulfate conjugate were significantly decreased to 56.4% and 61.7% of the vehicle control group, respectively. These results suggest that rutaecarpine might cause changes in the pharmacokinetic parameters of APAP in rats.
Caffeine induces cytochrome P4501A2: induction of CYP1A2 by tea in rats
  • L Chen
  • F Y Bondoc
  • M J Lee
  • A H Hussin
  • P E Thomas
  • L. Chen
A new class of COX-2 inhibitor, rutaecarpine from Evodia rutaecarpa
  • T C Moon
  • M Murakami
  • I Kudo
  • K H Son
  • H P Kim
  • S S Kang
  • T. C. Moon