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CYP3A4
Kinds of CYP3A4 Terms modified by CYP3A4 Selected AbstractsBench to Bedside: Pharmacogenomics, Adverse Drug Interactions, and the Cytochrome P450 SystemACADEMIC EMERGENCY MEDICINE, Issue 12 2005Rishi Sikka MD As physicians attempt to improve the quality of health care, one area of particular concern has been preventable medical errors from adverse drug interactions. The cytochrome P450 family of enzymes has been implicated in a large number of these preventable, adverse drug interactions. This report reviews the basic biochemistry and pharmacogenomics underlying the reactions catalyzed by the cytochrome P450 family of enzymes. An emphasis is placed on the phenotypic variations within a population and the resulting clinical effects. In addition, six members of the cytochrome P450 superfamily that are responsible for the metabolism of the majority of pharmaceutical agents are profiled in detail. These enzymes, CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1, and CYP1A2, are reviewed with regard to their phenotypic variation in the population and the resulting clinical and therapeutic implications. [source] Capillary electrophoretic investigation of the enantioselective metabolism of propafenone by human cytochrome P-450 SUPERSOMES: Evidence for atypical kinetics by CYP2D6 and CYP3A4ELECTROPHORESIS, Issue 8 2006Minoo Afshar Abstract An enantioselective CE method was used to identify the ability of CYP450 enzymes and their stereoselectivity in catalyzing the transformation of propafenone (PPF) to 5-hydroxy-propafenone (5OH-PPF) and N -despropyl-propafenone (NOR-PPF). Using in,vitro incubations with single CYP450 enzymes (SUPERSOMES), 5OH-PPF is shown to be selectively produced by CYP2D6 and N -dealkylation is demonstrated to be mediated by CYP2D6, CYP3A4, CYP1A2, and CYP1A1. For the elucidation of kinetic aspects of the metabolism with CYP2D6 and CYP3A4, incubations with individual PPF enantiomers and racemic PPF were investigated. With the exception of the dealkylation in presence of R -PPF only, which can be described by the Michaelis,Menten model, all CYP2D6-induced reactions were found to follow autoactivation kinetics. For CYP3A4, all NOR-PPF enantiomer formation rates as function of PPF enantiomer concentration were determined to follow substrate inhibition kinetics. The formation of NOR-PPF by the different enzymes is stereoselective and is reduced significantly when racemic PPF is incubated. Clearance values obtained for CYP3A4 dealkylation are stereoselective whereas those of CYP2D6 hydroxylation are not. This paper reports the first investigation of the PPF hydroxylation and dealkylation kinetics by the CYP2D6 enzyme and represents the first report in which enantioselective CE data provide the complete in,vitro kinetics of metabolic steps of a drug. [source] A Comparative Pharmacokinetic Study in Healthy Volunteers of the Effect of Carbamazepine and Oxcarbazepine on Cyp3a4EPILEPSIA, Issue 3 2007Astrid-Helene Andreasen Summary:,Purpose: Carbamazepine (CBZ) and oxcarbazepine (OXCZ) are well-known inducers of drug metabolism via CYP3A4. Indirect interaction studies and clinical experience suggest that CBZ has a stronger potential in this regard than OXCZ. However this has never been subject to a direct comparative study. We performed a study in healthy volunteers to investigate the relative inductive effect of CBZ and OXCZ on CYP3A4 activity using the metabolism of quinidine as a biomarker reaction. Methods: Ten healthy, male volunteers participated in an open, randomized crossover study consisting of two periods separated by a 4-week wash-out period. The subjects received 1200 mg oral OXCZ daily for 17 days and 800 mg oral CBZ for 17 days. A single 200 mg oral dose of quinidine was administered at baseline and following administration of CBZ and OXCZ. Outcome parameters were the formation clearance of 3-hydroxyquinidine dose and the ratio of the AUCs of 3-hydroxyquinidine to quinidine. Results: Formation clearance of 3-hydroxyquinidine was increased by means of 89% (CI: 36,164; p = 0.0022) and 181% (CI: 120,260, p < 0.0001) after treatment with OXCZ and CBZ, respectively, compared to baseline. The relative inductive effect of CBZ was 46% higher than for OXCZ. AUC ratio increased by means of 161% (CI: 139,187, p < 0.0001) (OXCZ) and 222% (CI: 192,257, p < 0.0001) (CBZ). Quinidine Cmax decreased by means of 29% (CI: 16,40, p = 0.0018) (OXCZ) and 33% (CI: 18,45, p = 0.0020) (CBZ). T½ decreased by means of 12% (CI: 6,17, p < 0.0014) (OXCZ) and 32% (CI: 25,38, p < 0.0001) (CBZ). tmax was not changed in either period. Conclusion: We confirm a clinically significant inductive effect of both OXCZ and CBZ. The inductive effect of CBZ was about 46% higher than that of OXCZ, a difference that may be of clinical relevance. [source] Dose-dependent Induction of Cytochrome P450 (CYP) 3A4 and Activation of Pregnane X Receptor by TopiramateEPILEPSIA, Issue 12 2003Srikanth C. Nallani Summary:,Purpose: In clinical studies, topiramate (TPM) was shown to cause a dose-dependent increase in the clearance of ethinyl estradiol. We hypothesized that this interaction results from induction of hepatic cytochrome P450 (CYP) 3A4 by TPM. Accordingly, we investigated whether TPM induces CYP3A4 in primary human hepatocytes and activates the human pregnane X receptor (hPXR), a nuclear receptor that serves as a regulator of CYP3A4 transcription. Methods: Human hepatocytes were treated for 72 h with TPM (10, 25, 50, 100, 250, and 500 ,M) and known inducers, phenobarbital (PB; 2 mM), and rifampicin (10 ,M). The rate of testosterone 6,-hydroxylation by hepatocytes served as a marker for CYP3A4 activity. The CYP3A4-specific protein and mRNA levels were determined by using Western and Northern blot analyses, respectively. The hPXR activation was assessed with cell-based reporter gene assay. Results: Compared with controls, TPM (50,500 ,M),treated hepatocytes exhibited a considerable increase in the CYP3A4 activity (1. 6- to 8.2-fold), protein levels (4.6- to 17.3-fold), and mRNA levels (1.9- to 13.3-fold). Comparatively, rifampicin (10 ,M) effected 14.5-, 25.3-, and a 20.3-fold increase in CYP3A4 activity, immunoreactive protein levels, and mRNA levels, respectively. TPM (50,500 ,M) caused 1.3- to 3-fold activation of the hPXR, whereas rifampicin (10 ,M) caused a 6-fold activation. Conclusions: The observed induction of CYP3A4 by TPM, especially at the higher concentrations, provides a potential mechanistic explanation of the reported increase in the ethinyl estradiol clearance by TPM. It also is suggestive of other potential interactions when high-dose TPM therapy is used. [source] Variable expression of CYP and Pgp genes in the human small intestineEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2003M. Lindell Abstract Background ,The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome P450 and P-Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes. Methods ,The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT-PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed. Results ,Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively. Conclusions ,Extensive interindividual variability is characteristic for the expression of drug-metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation. [source] Impact of inter-individual differences in drug metabolism and pharmacokinetics on safety evaluationFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2004J.L.C.M. Dorne Abstract Safety evaluation aims to assess the dose,response relationship to determine a dose/level of exposure for food contaminants below which no deleterious effect is measurable that is ,without appreciable health risk' when consumed daily over a lifetime. These safe levels, such as the acceptable daily intake (ADI) have been derived from animal studies using surrogates for the threshold such as the no-observed-adverse-effect-level (NOAEL). The extrapolation from the NOAEL to the human safe intake uses a 100-fold uncertainty factor, defined as the product of two 10-fold factors allowing for human variability and interspecies differences. The 10-fold factor for human variability has been further subdivided into two factors of 100.5 (3.16) to cover toxicokinetics and toxicodynamics and this subdivsion allows for the replacement of an uncertainty factor with a chemical-specific adjustment factor (CSAF) when compound-specific data are available. Recently, an analysis of human variability in pharmacokinetics for phase I metabolism (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, hydrolysis, alcohol dehydrogenase), phase II metabolism (N-acetyltransferase, glucuronidation, glycine conjugation, sulphation) and renal excretion was used to derive pathway-related uncertainty factors in subgroups of the human population (healthy adults, effects of ethnicity and age). Overall, the pathway-related uncertainty factors (99th centile) were above the toxicokinetic uncertainty factor for healthy adults exposed to xenobiotics handled by polymorphic metabolic pathways (and assuming the parent compound was the proximate toxicant) such as CYP2D6 poor metabolizers (26), CYP2C19 poor metabolizers (52) and NAT-2 slow acetylators (5.2). Neonates were the most susceptible subgroup of the population for pathways with available data [CYP1A2 and glucuronidation (12), CYP3A4 (14), glycine conjugation (28)]. Data for polymorphic pathways were not available in neonates but uncertainty factors of up to 45 and 9 would allow for the variability observed in children for CYP2D6 and CYP2C19 metabolism, respectively. This review presents an overview on the history of uncertainty factors, the main conclusions drawn from the analysis of inter-individual differences in metabolism and pharmacokinetics, the development of pathway-related uncertainty factors and their use in chemical risk assessment. [source] Functional interaction of intestinal CYP3A4 and P-glycoproteinFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2004Kari T. Kivistö Abstract Intestinal CYP3A4-mediated biotransformation and active efflux of absorbed drug by P-glycoprotein are major determinants of bioavailability of orally administered drugs. The hypothesis that CYP3A4 and P-glycoprotein may act in concert to limit oral drug bioavailability is attractive from a theoretical point of view. Evidence in support of such an interplay between CYP3A4 and P-glycoprotein comes mainly from a limited number of in vitro and animal studies. Obviously, it is a challenging task to demonstrate in vivo in humans that the function of CYP3A4 and P-glycoprotein in enterocytes is complementary, and results to directly support this concept remain elusive. However, CYP3A4 and P-glycoprotein are clearly an integral part of an intestinal defence system to protect the body against harmful xenobiotics, and drugs that are substrates of both proteins often have a low bioavailability after oral administration. The functional interaction of intestinal CYP3A4 and P-glycoprotein warrants additional study. Further understanding this interplay would be potentially useful during drug development to solve bioavailability problems of new drug entities. [source] Metabolic drug interactions with new psychotropic agentsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2003Edoardo Spina Abstract New psychotropic drugs introduced in clinical practice in recent years include new antidepressants, such as selective serotonin reuptake inhibitors (SSRI) and ,third generation' antidepressants, and atypical antipsychotics, i.e. clozapine, risperidone, olanzapine, quetiapine, ziprasidone and amisulpride. These agents are extensively metabolized in the liver by cytochrome P450 (CYP) enzymes and are therefore susceptible to metabolically based drug interactions with other psychotropic medications or with compounds used for the treatment of concomitant somatic illnesses. New antidepressants differ in their potential for metabolic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, while nefazodone is a potent inhibitor of CYP3A4. These antidepressants may be involved in clinically significant interactions when coadministered with substrates of these isoforms, especially those with a narrow therapeutic index. Other new antidepressants including sertraline, citalopram, venlafaxine, mirtazapine and reboxetine are weak in vitro inhibitors of the different CYP isoforms and appear to have less propensity for important metabolic interactions. The new atypical antipsychotics do not affect significantly the activity of CYP isoenzymes and are not expected to impair the elimination of other medications. Conversely, coadministration of inhibitors or inducers of the CYP isoenzymes involved in metabolism of the various antipsychotic compounds may alter their plasma concentrations, possibly leading to clinically significant effects. The potential for metabolically based drug interactions of any new psychotropic agent may be anticipated on the basis of knowledge about the CYP enzymes responsible for its metabolism and about its effect on the activity of these enzymes. This information is essential for rational prescribing and may guide selection of an appropriate compound which is less likely to interact with already taken medication(s). [source] Drug metabolism and disposition in childrenFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2003M. Strolin Benedetti Abstract Key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the pediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, bacterial colonization and probably P-glycoprotein are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein concentration and plasma protein characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and probably P-glycoprotein, mainly that present in the gut, liver and brain. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I enzymes [oxidative (e.g. cytochrome CYP3A7 vs. CYP3A4 and CYP1A2), reductive and hydrolytic enzymes] and phase II enzymes (e.g. N -methyltransferases and glucuronosyltransferases). Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the pediatric population compared with adults are glomerular filtration and tubular secretion. It would be important to generate information on the developmental aspects of renal P-glycoprotein and of other renal transporters as done and still being done with the different isozymes involved in drug metabolism. [source] In vitro effects of tacrolimus on human cytochrome P450FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 6 2002K. Lecointre Abstract Tacrolimus, a potent immunosuppressive drug, is known to be metabolized predominantly in the liver by cytochrome P450 3A (CYP3A). In order to determine the potential of tacrolimus to inhibit the metabolism of other drugs, we have investigated its inhibitory effects on specific cytochrome reactions. Specific substrates for the seven cytochromes (CYPs) 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4/5 were incubated with human hepatic microsome preparations with or without specific inhibitors or tacrolimus and the metabolites were detected by high-pressure liquid chromatography (HPLC) or fluorimetric methods. All the specific inhibitors reduced or abolished the specific CYP activity. Tacrolimus had no effect on any CYP at concentrations below 1 µm, while at higher concentrations it had a mild inhibitory effect on CYP3A4 and 3A5. These observations suggest that tacrolimus is unlikely to potentiate the effect of coadministered drugs through inhibition of their metabolism in the liver. [source] Lopinavir/ritonavir monotherapy as maintenance treatment in HIV-infected individuals with virological suppression: results from a pilot study in BrazilHIV MEDICINE, Issue 5 2008E Sprinz Objective The aim of the study was to evaluate the possibility of using lopinavir/ritonavir (LPV/RTV) alone as maintenance therapy in HIV-infected individuals with virological suppression. Design This was a single-armed single-centre pilot trial. Methods Asymptomatic HIV-infected patients on highly active antiretroviral therapy (HAART) including LPV/RTV, and with plasma HIV RNA <40 copies/mL for at least 6 months, were enrolled in the study, during which they continued with LPV/RTV alone. The intention was to recruit 25 patients to be followed for 2 years. Viral failure was defined as two consecutive HIV RNA measurements >40 copies/mL. Nadir and baseline CD4 cell counts, highest ever HIV RNA load, time with undetectable viraemia before monotherapy, number of previous antiretroviral (ARV) regimens, and gene polymorphism at CYP3A4 and CYP3A5 were evaluated. Results All patients (27) completed the study. Their median age was 43 years, and 66% were men. Ten patients (37%) failed to maintain virological suppression (the median time to HIV rebound was 10.5 months, with a range of 4,23 months). One patient developed full resistance to LPV and another developed neurocognitive impairment while on LPV/RTV which improved after HAART reintroduction. There were no differences between failures and nonfailures according to the analysed parameters. Patients with viral failure were successfully resuppressed. Conclusions LPV/RTV maintenance therapy was associated with 37% failure, a higher than expected failure rate. In order to ensure that unnecessary risks are not being taken in patients on LPV/RTV, this finding should be further evaluated in large randomized trials for longer periods of follow-up. [source] CYP3A4 and pregnane X receptor humanized miceJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 4 2007Frank J. Gonzalez Abstract Marked species differences exist in P450 expression and activities. In order to produce mouse models that can be used to more accurately predict human drug and carcinogen metabolism, P450- and xenobiotic receptor humanized mice are being prepared using bacterial artificial chromosomes (BAC) and P1 phage artificial chromosomes (PAC) genomic clones. In some cases, transgenic mice carrying the human genes are bred with null-mice to produce fully humanized mice. Mice expressing human CYP1A1, CYP1A2, CYP2E1, CYP2D6, CYP3A4, and CYP3A7 were generated and characterized. Studies with the CYP3A4-humanized (hCYP3A4) mouse line revealed new information on the physiological function of this P450 and its role in drug metabolism in vivo. With this mouse line, CYP3A4, under certain circumstances, was found to alter the serum levels of estrogen resulting in deficient lactation and low pup survival as a result of underdeveloped mammary glands. This hCYP3A4 mouse established the importance of intestinal CYP3A4 in the pharmacokinetics of orally administered drugs. The hCYP3A4 mice were also used to establish the mechanisms of potential gender differences in CYP3A4 expression (adult female > adult male) that could account for human gender differences in drug metabolism and response. The pregnane X receptor (PXR) is also involved in induction of drug metabolism through its target genes including CYP3A4. Since species differences exist in ligand specificity between human and mice, a PXR -humanized mouse (hPXR) was produced that responds to human PXR activators such as rifampicin but does not respond to the rodent activator pregnenalone 16,-carbonitrile. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:158,162, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20173 [source] Inhibition of fipronil and nonane metabolism in human liver microsomes and human cytochrome P450 isoforms by chlorpyrifosJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 2 2007Hyun Joo Abstract Previous studies have established that chlorpyrifos (CPS), fipronil, and nonane can all be metabolized by human liver microsomes (HLM) and a number of cytochrome P450 (CYP) isoforms. However, metabolic interactions between these three substrates have not been described. In this study the effect of either coincubation or preincubation of CPS with HLM or CYP isoforms with either fipronil or nonane as substrate was investigated. In both co- and preincubation experiments, CPS significantly inhibited the metabolism of fipronil or nonane by HLM although CPS inhibited the metabolism of fipronil more effectively than that of nonane. CPS significantly inhibited the metabolism of fipronil by CYP3A4 as well as the metabolism of nonane by CYP2B6. In both cases, preincubation with CPS caused greater inhibition than coincubation, suggesting that the inhibition is mechanism based. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:76,80, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20161 [source] Effect of silybin and its glycosides on the expression of cytochromes P450 1A2 and 3A4 in primary cultures of human hepatocytesJOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 3 2005Pavel Kosina Abstract Four ,-glycosides of flavonoligan silybin, i.e. silybin ,-galactoside, silybin ,-glucoside, silybin ,-maltoside, silybin ,-lactoside were synthesized in order to improve silybin water solubility and bioavailability (K,en et al., J Chem Soc, Perkin Trans 1, 2467,2474, 1997). The presented paper deals with the effect of silybin and its synthetic ,-glycosides on the expression of two major cytochrome P450 isoforms, CYP1A2 and CYP3A4. Primary cultures of human hepatocytes were the model of choice. mRNAs were analyzed using Northern blot and P-radiolabelled probes. CYP protein content was determined by immunoblotting using specific antibodies. Silybin and its ,-glycosides do not induce expression of CYP1A2 and CYP3A4. Tested compounds did not affect inducible expression of CYP1A2 and CYP3A4 by dioxin and rifampicin, respectively, as evaluated at the level of mRNAs and proteins. Silybin and its ,-glycosides do not interfere with the expression of CYP1A2 and CYP3A4, are not likely to produce drug,drug interactions in terms of the inducibility of two important cytochromes P450. © 2005 Wiley Periodicals, Inc. J Biochem Mol Toxicol 19:149,153, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20066 [source] CYP3A4 is a Human Microsomal Vitamin D 25-Hydroxylase,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 4 2004Ram P Gupta Abstract The human hepatic microsomal vitamin D 25-hydroxylase protein and gene have not been identified with certainty. Sixteen hepatic recombinant microsomal enzymes were screened for 25-hydroxylase activity; 11 had some 25-hydroxylase activity, but CYP3A4 had the highest activity. In characterized liver microsomes, 25-hydroxylase activity correlated significantly with CYP3A4 testosterone 6,-hydroxylase activity. Activity in pooled liver microsomes was inhibited by known inhibitors of CYP3A4 and by an antibody to CYP3A2. Thus, CYP3A4 is a hepatic microsomal vitamin D 25-hydroxylase. Introduction: Studies were performed to identify human microsomal vitamin D-25 hydroxylase. Materials and Methods: Sixteen major hepatic microsomal recombinant enzymes derived from cytochrome P450 cDNAs expressed in baculovirus-infected insect cells were screened for 25-hydroxylase activity with 1,-hydroxyvitamin D2 [1,(OH)D2], 1,-hydroxyvitamin D3 [1,(OH)D3], vitamin D2, and vitamin D3 as substrates. Activity was correlated with known biological activities of enzymes in a panel of 12 characterized human liver microsomes. The effects of known inhibitors and specific antibodies on activity also were determined. Results: CYP3A4, the most abundant cytochrome P450 enzyme in human liver and intestine, had 7-fold greater activity than that of any of the other enzymes with 1,(OH)D2 as substrate. CYP3A4 25-hydroxylase activity was four times higher with 1,(OH)D2 than with 1,(OH)D3 as substrate, was much less with vitamin D2, and was not detected with vitamin D3. 1,(OH)D2 was the substrate in subsequent experiments. In a panel of characterized human liver microsomes, 25-hydroxylase activity correlated with CYP3A4 testosterone 6,-hydroxylase activity (r = 0.93, p < 0.001) and CYP2C91 diclofenac 4,-hydroxylase activity (r = 0.65, p < 0.05), but not with activity of any of the other enzymes. Activity in recombinant CYP3A4 and pooled liver microsomes was dose-dependently inhibited by ketoconazole, troleandomycin, isoniazid, and ,-naphthoflavone, known inhibitors of CYP3A4. Activity in pooled liver microsomes was inhibited by antibodies to CYP3A2 that are known to inhibit CYP3A4 activity. Conclusion: CYP3A4 is a vitamin D 25-hydroxylase for vitamin D2 in human hepatic microsomes and hydroxylates both 1,(OH)D2 and 1,(OH)D3. [source] CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxineJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2006M. E. E. Shams PhD Summary Background:, Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O -desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N -desmethylvenlafaxine (NDV). Objectives:, The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome. Method:, In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale. Results:, There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1·8 and the 10th and 90th percentiles 0·3 and 5·2, respectively. Individuals with ODV/V ratios below 0·3 were all identified as poor metabolizers (PM), with the genotypes *6/*4 (n = 1), *5/*4 (n = 2) or *6/*6 (n = 1). Individuals with ratios above 5·2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1·1 ± 0·8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4·8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0·3 had more side effects (P < 0·005) and reduced serum concentrations of sodium (P < 0·05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes. Conclusion:, The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects. [source] Inhibition of human cytochrome P450 isoforms and NADPH-CYP reductase in vitro by 15 herbal medicines, including Epimedii herbaJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2006K. H. Liu PhD Summary Objective:, We evaluated the potential of 15 herbal medicines (HMs), commonly used in Korea, to inhibit the catalytic activities of several cytochrome P450 (CYP) isoforms and microsomal NADPH-CYP reductase. Methods:, The abilities of 1,1000 ,g/mL of freeze-dried aqueous extracts of 15 HMs to inhibit phenacetin O -deethylation (CYP1A2), tolbutamide 4-methylhydroxylation (CYP2C9), S -mephenytoin 4,-hydroxylation (CYP2C19), dextromethorphan O -demethylation (CYP2D6), chlorzoxazone 6-hydroxylation (CYP2E1), midazolam 1-hydroxylation (CYP3A4) and NADPH-CYP reductase were tested using human liver microsomes. Results:, The HMs Epimedii herba, Glycyrrhizae radix and Leonuri herba inhibited one or more of the CYP isoforms or NADPH-CYP reductase. Of the three HMs, Epimedii herba extracts were the most potent inhibitors of several CYP isoforms (IC50 67·5 ,g/mL for CYP2C19, 104·8 ,g/mL for CYP2E1, 110·9 ,g/mL for CYP2C9, 121·9 ,g/mL for CYP3A4, 157·8 ,g/mL for CYP2D6 and 168·7 ,g/mL for CYP1A2) and NADPH-CYP reductase (IC50 185·9 ,g/mL). Conclusion:, These results suggest that some of the HMs used in Korea have the potential to inhibit CYP isoforms in vitro. Although the plasma concentrations of the active constituents of the HMs were not determined, some herbs could cause clinically significant interactions because the usual doses of those individual herbs are several grams of freeze-dried extracts. Controlled trials to test the significance of these results are necessary. [source] Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteersJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2005W. Ridtitid MD FCFPT Summary Background:, Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine. Objective:, To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy Thai male volunteers. Methods:, In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day period. Plasma mefloquine and mefloquine carboxylic metabolite concentrations during 56 days were measured by a modified and validated high-performance liquid chromatographic method with UV detection. Results:, Co-administration with ketoconazole markedly increased the mean values of mefloquine AUC0,t, t1/2, and Cmax when compared with mefloquine alone by 79% (P < 0·001), 39% (P < 0·05) and 64% (P < 0·001) respectively. The AUC0,t,, and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0·05) and 31% (P < 0·05), respectively when compared with mefloquine alone. Conclusions:, Co-administration with ketoconazole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloquine is co-administered with ketoconazole, drug,drug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy. [source] In vitro assessment of cytochrome P450 inhibition: Strategies for increasing LC/MS-based assay throughput using a one-point IC50 method and multiplexing high-performance liquid chromatographyJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2007Tong Lin Abstract A fast and robust LC/MS-based cytochrome P450 (CYP) inhibition assay, using human liver microsomes, has been fully developed and validated for the major human liver CYPs. Probe substrates were phenacetin, diclofenac, S-mephenytoin, and dextromethorphan for CYP1A2, CYP2C9, CYP2C19, and CYP2D6, respectively. Midazolam and testosterone were chosen for CYP3A4. Furafylline, sulfaphenazole, tranylcypromine, quinidine, and ketoconazole were identified as positive control inhibitors for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. To increase the throughput of the assay, a one-point method was developed, using data from CYP inhibition assays conducted at one concentration (i.e., 10 µM), to estimate the drug concentration at which the metabolism of the CYP probe substrate was reduced by 50% (IC50). The IC50 values from the one-point assay were validated by correlating the results with IC50 values that were obtained with a traditional eight-point concentration,response curve. Good correlation was achieved with the slopes of the trendlines between 0.95 and 1.02 and with R2 between 0.77 and 1.0. Throughput was increased twofold by using a Cohesive multiplexing high-performance liquid chromatography system. The one-point IC50 estimate is useful for initial compound screening, while the full concentration,response IC50 method provides detailed CYP inhibition data for later stages of drug development. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2485,2493, 2007 [source] Stereoselective disposition of talinolol in manJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2002Michael Zschiesche Abstract The disposition of the ,-blocking drug talinolol is controlled by P-glycoprotein in man. Because talinolol is marketed as a racemate, we reevaluated the serum-concentration time profiles of talinolol of a previously published study with single intravenous (30 mg) and repeated oral talinolol (100 mg for 14 days) before and after comedication of rifampicin (600 mg per day for 9 days) in eight male healthy volunteers (age 22,26 years, body weight 67,84 kg) with respect to differences in the kinetic profiles of the two enantiomers S(,) talinolol and R(+) talinolol. Additionally, the metabolism of talinolol in human liver microsomes was examined. After oral administration, S(,) talinolol was slightly less absorbed and faster eliminated than R(+) talinolol. The absolute bioavailabilty of the R(+) enantiomer of talinolol was slightly but significantly higher than of its S(,) enantiomer. Coadministration of rifampicin further intensified this difference in the disposition of R(+) and S(,) talinolol (p,<,0.05). Formation of 4-trans hydroxytalinolol was the major metabolic pathway in human liver microsomes. All Clint values of S(,) were higher than of R(+) talinolol; 0.1 ,M ketoconazole inhibited the formation of all metabolites. In conclusion, the stereoselectivity of talinolol disposition is of minor importance, and most likely caused by presystemic biotransformation via CYP3A4. The less active R(+) talinolol might be suitable for phenotyping P-glycoprotein expression in man. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:303,311, 2002 [source] Effects of myricetin, an antioxidant, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats: possible role of cytochrome P450 3A4, cytochrome P450 2C9 and P-glycoprotein inhibition by myricetinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2010Dong-Hyun Choi Abstract Objectives, The effects of myricetin, a natural flavonoid, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, were investigated in rats. Losartan and myricetin interact with cytochrome P450 (CYP) enzymes and P-glycoprotein, and the increase in the use of health supplements may result in myricetin being taken concomitantly with losartan as a combination therapy to treat or prevent cardiovascular diseases. Methods, The pharmacokinetic parameters of losartan and EXP-3174 were determined after oral administration of losartan (9 mg/kg) to rats in the presence or absence of myricetin (0.4, 2 and 8 mg/kg). The effects of myricetin on P-glycoprotein as well as CYP3A4 and CYP2C9 activity were also evaluated. Key findings, Myricetin inhibited CYP3A4 and CYP2C9 enzyme activity with a 50% inhibition concentration of 7.8 and 13.5 µm, respectively. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-glycoprotein in a concentration-dependent manner. The pharmacokinetic parameters of losartan were significantly altered by myricetin compared with the control. The presence of myricetin (2 or 8 mg/kg) increased the area under the plasma concentration,time curve of losartan by 31.4,61.1% and peak plasma concentration of losartan by 31.8,50.2%. Consequently, the absolute bioavailability of losartan in the presence of myricetin increased significantly (P < 0.05, 2 mg/kg; P < 0.01, 8 mg/kg) compared with the control. There was no significant change in the time to reach the peak plasma concentration, apparent volume of distribution at steady state or terminal half-life of losartan in the presence of myricetin. Furthermore, concurrent use of myricetin (8 mg/kg) significantly decreased the metabolite,parent area under the plasma concentration,time curve ratio by 20%, implying that myricetin may inhibit the CYP-mediated metabolism of losartan to its active metabolite, EXP-3174. Conclusions, The enhanced bioavailability of losartan may be mainly due to inhibition of the CYP3A4- and CYP2C9-mediated metabolism of losartan in the small intestine or in the liver, and the P-glycoprotein efflux pump in the small intestine by myricetin. [source] Prediction of human pharmacokinetics,gut-wall metabolismJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2007Urban Fagerholm Intestinal mucosal cells operate with different metabolic and transport activity, and not all of them are involved in drug absorption and metabolism. The fraction of these cells involved is dependent on the absorption characteristics of compounds and is difficult to predict (it is probably small). The cells also appear comparably impermeable. This shows a limited applicability of microsome intrinsic clearance (CLint)-data for prediction of gut-wall metabolism, and the difficulty to predict the gut-wall CL (CLGW) and extraction ratio (EGW). The objectives of this review were to evaluate determinants and methods for prediction of first-pass and systemic EGW and CLGW in man, and if required and possible, develop new simple prediction methodology. Animal gut-wall metabolism data do not appear reliable for scaling to man. In general, the systemic CLGW is low compared with the hepatic CL. For a moderately extracted CYP3A4-substrate with high permeability, midazolam, the gut-wall/hepatic CL-ratio is only 1/35. This suggests (as a general rule) that systemic CLGW can be neglected when predicting the total CL. First-pass EGW could be of importance, especially for substrates of CYP3A4 and conjugating enzymes. For several reasons, including those presented above and that blood flow based models are not applicable in the absorptive direction, it seems poorly predicted with available methodology. Prediction errors are large (several-fold on average; maximum-15-fold). A new simple first-pass EGW -prediction method that compensates for regional and local differences in absorption and metabolic activity has been developed. It has been based on human cell in-vitro CLint and fractional absorption from the small intestine for reference (including verapamil) and test substances, and in-vivo first-pass EGW -data for reference substances. First-pass EGW -values for CYP3A4-substrates with various degrees of gastrointestinal uptake and CLint and a CYP2D6-substrate were well-predicted (negligible errors). More high quality in-vitro CLint - and in-vivo EGW -data are required for further validation of the method. [source] Purification of citrus limonoids and their differential inhibitory effects on human cytochrome P450 enzymesJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 9 2007Shibu M Poulose Abstract Recent studies demonstrated that citrus limonoids and flavonoids possess numerous health promoting properties. In the present study, glucosides of limonoids and flavonoids were purified from citrus molasses and limonoid aglycones from citrus seeds. Glucosides were separated on styrene (divinylbenzene), Q-sepharose resins with increasing concentration of sodium chloride. A pH-dependent cold precipitation was carried out for the isolation of naringin in large quantity. Major aglycones such as limonin and nomilin were isolated from seeds by direct crystallization and minor limonoids were purified by vacuum liquid chromatography. The structures of the isolated compounds were confirmed by NMR spectra. Individual limonoids were tested for O -dealkylase and hydroxylase activities of human cytochrome P450 (CYP) isoenzymes such as CYP1A2, CYP1B1, CYP3A4 and CYP19, using ethoxyresorufin, methoxyresorufin and dibenzylfluorescein as substrates. Partial to high inhibition of CYPs was observed in dose-dependent assays. Significant (P < 0.001) reductions in enzyme activities were observed with purified compounds above 2 µmol. Kinetic analyses indicated that limonin glucoside inhibited CYP19 competitively (IC50, 7.1 µ mol L,1), whereas Nomilinic acid glucoside inhibited it noncompetitively (IC50, 9.4 µ mol,1). Nomilinic acid glucoside was the most potent limonoid, with an overall IC50 of < 10 µ mol, for all the enzymes tested. The differential inhibition of CYPs can be ascribed to structural variations of the limonoid nucleus. Limonoid inhibition of key CYPs involved in carcinogenesis supports growing evidence that citrus limonoids act as anticancer agents. Copyright © 2007 Society of Chemical Industry [source] Influence of genetic variation in CYP3A4 and ABCB1 on dose decrease or switching during simvastatin and atorvastatin therapy,PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 1 2010Matthijs L. Becker PharmD Abstract Purpose Simvastatin and atorvastatin are metabolized by the CYP3A4 enzyme and transported by the ABCB1 transporter. We studied whether the polymorphism CYP3A4*1B and the polymorphisms C1236T, G2677A/T and C3435T in the ABCB1 gene were associated with a decrease of the prescribed dose or a switch to another cholesterol lowering drug during simvastatin and atorvastatin therapy. These events may indicate that statin plasma levels were too high and resulted in an adverse drug reaction or a too strong reduction in cholesterol level. Methods We identified 1239 incident simvastatin and atorvastatin users in the Rotterdam Study, a population-based cohort study. Associations between the polymorphisms in the CYP3A4 and ABCB1 gene and the time to a decrease in dose or a switch to another cholesterol lowering drug were studied using Cox proportional hazards. Results Simvastatin and atorvastatin users with the CYP3A4*1B variant G allele had a lower risk (HR 0.46; 95%CI 0.24,0.90) for these events than users with the wild-type AA genotype. No significant associations were found for the ABCB1 polymorphisms. The association with the CYP3A4*1B polymorphism was found in women (HR 0.33; 95%CI 0.12,0.89) and was non-significant in men (HR 0.69 95%CI 0.28,1.70). This association was stronger in patients with the ABCB1 3435T variant allele versus the G allele. Conclusion In simvastatin and atorvastatin users, the CYP3A4*1B G allele is associated with a lower risk of elevated statin plasma levels, particularly in women and in users with the ABCB1 3435T variant allele. Copyright © 2009 John Wiley & Sons, Ltd. [source] Woran sollte man denken bei der Gabe von Johanniskrautpräparaten?: Unerwünschte Arzneimittelwirkungen und -interaktionenPHARMAZIE IN UNSERER ZEIT (PHARMUZ), Issue 3 2003Andreas Johne Dr. med. Aufgrund klinischer Daten ist die Gabe von Johanniskrautextrakten bei Patienten abzulehnen, die Arzneimittel mit geringer therapeutischer Breite einnehmen müssen (z. B. die Immunsuppressiva Ciclosporin und Tacrolimus, Antikoagulantien vom Coumarin-Typ, Virustatika wie HIV-Proteaseinhibitoren und Nichtkompetitive-Reverse-Transkriptase-Inhibitoren sowie Chemotherapeutika wie Irinotecan). Eine Interaktion mit oralen Kontrazeptiva erscheint möglich. Die pharmakokinetischen Interaktionen nach wiederholter Gabe von Johanniskrautextrakten beruhen auf einer Erhöhung der Aktivität fremdstoffmetabolisierender Enzyme (CYP3A4) und von Transportproteinen (MDR1-Produkt P-Glycoprotein). Eine Kombination mit weiteren Antidepressiva sollte aufgrund des möglichen Auftretens eines Serotonin-Syndroms unterbleiben. Zudem können bestimmte therapeutische Situationen, wie beispielsweise eine Lasertherapie, das Risiko phototoxischer Reaktionen erhöhen. Unter Beachtung dieser Risiken ist die Gabe von Johanniskrautextrakt jedoch eine sichere und wirkungsvolle Alternative zur Behandlung leichter bis mittelstarker depressiver Episoden. [source] In vitro inhibition of CYP3A4 by herbal remedies frequently used by cancer patientsPHYTOTHERAPY RESEARCH, Issue 7 2009Silje Engdal Abstract The herbal remedies Natto K2, Agaricus, mistletoe, noni juice, green tea and garlic, frequently used by cancer patients, were investigated for their in vitro inhibition potential of cytochrome P-450 3A4 (CYP3A4) metabolism. To our knowledge, only garlic and green tea had available data on the possible inhibition of CYP3A4 metabolism. Metabolic studies were performed with human c-DNA baculovirus expressed CYP3A4. Testosterone was used as a substrate and ketoconazole as a positive quantitative inhibition control. The formation of 6- , -OH-testosterone was quantified by a validated HPLC methodology. Green tea was the most potent inhibitor of CYP3A4 metabolism (IC50: 73 µg/mL), followed by Agaricus, mistletoe and noni juice (1324, 3594, >10 000 µg/mL, respectively). All IC50 values were high compared with those determined for crude extracts of other herbal remedies. The IC50/IC25 ratios for the inhibiting herbal remedies ranged from 2.15 to 2.67, indicating similar inhibition profiles of the herbal inhibitors of CYP3A4. Garlic and Natto K2 were classified as non-inhibitors. Although Agaricus, noni juice, mistletoe and green tea inhibited CYP3A4 metabolism in vitro, clinically relevant systemic or intestinal interactions with CYP3A4 were considered unlikely, except for a probable inhibition of intestinal CYP3A4 by the green tea product. Copyright © 2009 John Wiley & Sons, Ltd. [source] Real time monitoring of drug metabolic enzyme response inside human hepatoma GS-3A4-HepG2 cells by means of electrochemical impedance measurementPOLYMERS FOR ADVANCED TECHNOLOGIES, Issue 5 2004Masaaki Kobayashi Abstract Cytochrome P-450s (CYPs) are important biopolymers for the maintenance of cellular function. If metabolic activity of the CYP in the cells can be estimated, so can the function of metabolism, which is closer to the organism. In this research, the method of measuring the drug metabolic activity inside the cell by making use of an electrochemical technique was examined. Human hepatoma GS-3A4-HepG2 cells of which the cytochrome P-4503A4 (CYP3A4) drug metabolic activity is found to be the same as that of primary hepatocytes were used in the experiment. The GS-3A4-HepG2 cells were cultured on an indium-tin oxide (ITO) electrode until they became confluent. Substrate testosterone and inhibitor ketoconazole of CYP3A4 were exposed to cells cultured on an ITO electrode, and the reaction was observed by noting the electrochemical impedance measurement. Impedance was decomposed into the resistance component and the reactance component, and each was examined in detail. As a result, according to testosterone concentration change, there was a remarkable time change in the reactance component. A similar impedance measurement was done by using human hepatoma HepG2 cells in which the drug metabolic activity had extremely decreased. Nevertheless, no time change in the reactance component that was noticed in GS-3A4-HepG2 cells was observed. Next, the amount of metabolite in the solution after impedance measurement was measured by means of liquid chromatography-tandem mass spectroscopy (LC-MS/MS). In the experiment with GS-3A4-HepG2 cells, a testosterone concentration-dependent correlation was observed between the reactance component change and the amount of metabolite. But, in the impedance measurement by ketoconazole, the change in reactance components was not observed in either the GS-3A4-HepG2 cells or the HepG2 cells. Ketoconazole and the heme iron in CYP3A4 effect the coordination bond, but ketoconazole was not metabolized by CYP3A4. It was confirmed that the time change in the reactance component which was caused by the testosterone was detected neither in the cells that take up the substrate, nor in the coordination bond between the CYP enzyme and the drug. Therefore, the time change in the remarkable reactance component observed by this electrochemical impedance measurement is dependent on drug metabolic activity. An electrochemical drug metabolic activity measuring method with the human hepatoma GS-3A4-HepG2 cells was able to be established. Copyright © 2004 John Wiley & Sons, Ltd. [source] Combined Therapy with Atorvastatin and Calcineurin Inhibitors: No Interactions with TacrolimusAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2005W. P. D. Lemahieu Increased systemic exposure to statins and consequent risk for complications has been reported in patients concomitantly treated with cyclosporin A (CsA). This has been ascribed to inhibition of drug catabolism by cytochrome P450 3A4 (CYP3A4) or drug transport by P-glycoprotein (PGP) and organic anion transporting polypeptide (OATP1B1). It is not known whether the combination of statins and tacrolimus (Tac) also suffers from this drawback. Therefore, a pharmacokinetic study of atorvastatin and its metabolites was performed in 13 healthy volunteers after 4 days' treatment, and after short (12 h) concomitant exposure to CsA and Tac. A complementary assessment of overall CYP, and hepatic and intestinal CYP3A4 + PGP activity was performed after each treatment episode and compared to baseline (no drugs). Systemic exposure to atorvastatin acid and its metabolites was significantly increased when administered with CsA. In contrast, intake of Tac did not have any impact on atorvastatin pharmacokinetics. Concomitantly, a profound decrease of hepatic and intestinal PGP and an increase of intestinal CYP3A4 were noted with CsA, whereas no effect was seen after atorvastatin therapy with or without Tac. Based on these findings treatment with Tac appears a safer option for patients needing a combination of statins and calcineurin inhibitors. [source] Sunitinib malate in the treatment of renal cell carcinoma and gastrointestinal stromal tumor: Recommendations for patient management,ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 4 2007Jayesh DESAI Abstract Sunitinib malate (SU011248, Sutent®[Pfizer]) is an oral multitargeted tyrosine kinase inhibitor with efficacy against renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Sunitinib has been approved by various regulatory authorities for treatment of advanced RCC and unresectable and/or malignant GIST following failure of imatinib mesylate treatment due to resistance or intolerance. Sunitinib is generally well tolerated, with most side-effects being mild to moderate. The most common adverse events are lethargy, diarrhea, stomatitis, hand,foot syndrome and hypertension. Uncommon but important adverse effects are hypothyroidism and hematological toxicity (neutropenia and thrombocytopenia), which require monitoring. Caution is recommended when using concurrent inhibitors or inducers of CYP3A4. The frequency and severity of side-effects often correlates with increased drug exposure. In clinical trials, side-effects seldom led to treatment discontinuation. This paper summarizes the published literature and provides recommendations for patient assessments and management of treatment-related side-effects. [source] The Role of Human CYP2C8 and CYP2C9 Variants in Pioglitazone Metabolism In VitroBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2009Eugen Muschler The present study was conducted to further clarify the role of individual CYPs and of the CYP2C8/9 polymorphisms in the primary metabolism of pioglitazone in vitro. Pioglitazone (2,400 ,M) was incubated with isolated cytochrome P450 enzymes or human liver microsomes, some of them carrying either the CYP2C8*3/*3 genotype (and also the CYP2C9*2/*2 genotype) or the CYP2C8*1/*1 genotype (five samples each). The formation of the primary pioglitazone metabolite M-IV was monitored by HPLC. Enzyme kinetics were estimated assuming a single binding site. Mean intrinsic clearance of pioglitazone to the metabolite M-IV was highest for CYP2C8 and CYP1A2 with 58 pmol M-IV/min/nmol CYP P450/,M pioglitazone each, 53 for CYP2D6*1, 40 for CYP2C19*1, and 34 for CYP2C9*2, respectively. CYP2A6, CYP2B6, CYP2C9*1, CYP2C9*3, CYP2E1, CYP3A4 and CYP3A5 did not form quantifiable amounts of M-IV. CYP2C8*1/*1 microsomes (25 ± 4 pmol M-IV/min/mg protein/,M pioglitazone) showed lower intrinsic clearance of pioglitazone than CYP2C8*3/*3 microsomes (35 ± 9, p = 0.04). In all samples, metabolite formation showed substrate inhibition, while pioglitazone did not inhibit CYP2C8-mediated paclitaxel metabolism. CYP2C8, CYP1A2 and CYP2D6 are major CYPs forming M-IV in vitro. The higher activity of CYP2C8*3/CYP2C9*2 microsomes may result from a contribution of CYP2C9*2, or from differences in CYP2C8 expression. The evidence for substrate-specific inhibitory effects of pioglitazone on CYP2C-mediated metabolism needs to be tested in further studies. [source] | ||||||||||||||||||||||||||||