imatinib CYP2C8

The tyrosine kinase inhibitors sorafenib and imatinib are important in the treatment of a range of cancers but adverse effects in some patients necessitate dosage modifications. CYP3A4 has a major role in the oxidation of sorafenib to its N-oxide and N-hydroxymethyl metabolites and also acts in concert with CYP2C8 to mediate imatinib N-demethylation. CYP3A4 expression and function are impaired in patients with advanced liver disease, whereas the functions of CYP2C enzymes are relatively preserved. We evaluated the biotransformation of sorafenib and imatinib in well-characterized microsomal fractions from 17 control subjects and 19 individuals with hepatic cirrhosis of varying severity...

The antiplatelet drug clopidogrel is metabolized to an acyl- β -d-glucuronide, which causes time-dependent inactivation of CYP2C8. Our aim was to characterize the UDP-glucuronosyltransferase (UGT) enzymes that are responsible for the formation of clopidogrel acyl- β -d-glucuronide. Kinetic analyses and targeted inhibition experiments were performed using pooled human liver and intestine microsomes (HLMs and HIMs, respectively) and selected human recombinant UGTs based on preliminary screening. The effects of relevant UGT polymorphisms on the pharmacokinetics of clopidogrel were evaluated in 106 healthy volunteers...

Imatinib trough levels have been associated with its clinical effects. During chronic use of imatinib, CYP2C8 becomes an important metabolizing enzyme because of cytochrome P450 3A4 (CYP3A4) autoinhibition. Single nucleotide polymorphisms (SNPs) in CYP2C8 may affect imatinib trough levels. This study investigates the effect of common CYP2C8 polymorphisms [*1B (rs7909236), *1C (rs17110453), *3 (rs11572080 and rs10509681), and *4 (rs1058930)] on steady-state trough levels imatinib during chronic imatinib use in 43 patients with chronic myeloid leukemia or gastrointestinal stromal tumors...

OBJECTIVE: The aims of this study were to determine the effects of the CYP2C8*3 and *4 polymorphisms on imatinib metabolism and plasma imatinib concentrations in chronic myeloid leukaemia (CML) patients. METHODS: We genotyped 210 CML patients from the TIDELII trial receiving imatinib 400-800 mg/day for CYP2C8*3 (rs11572080, rs10509681) and *4 (rs1058930). Steady-state trough total plasma N-desmethyl imatinib (major metabolite):imatinib concentration ratios (metabolic ratios) and trough total plasma imatinib concentrations were compared between genotypes (one-way ANOVA with Tukey post hoc)...

During the last 10-15 years, cytochrome P450 (CYP) 2C8 has emerged as an important drug-metabolizing enzyme. CYP2C8 is highly expressed in human liver and is known to metabolize more than 100 drugs. CYP2C8 substrate drugs include amodiaquine, cerivastatin, dasabuvir, enzalutamide, imatinib, loperamide, montelukast, paclitaxel, pioglitazone, repaglinide, and rosiglitazone, and the number is increasing. Similarly, many drugs have been identified as CYP2C8 inhibitors or inducers. In vivo, already a small dose of gemfibrozil, i...

1. Imatinib is metabolized to N-desmethyl imatinib by CYPs 3A4 and 2C8. The effect of CYP2C8*3 genotype on N-desmethyl imatinib formation was unknown. 2. We examined imatinib N-demethylation in human liver microsomes (HLMs) genotyped for CYP2C8*3, in CYP2C8*3/*3 pooled HLMs and in recombinant CYP2C8 and CYP3A4 enzymes. Effects of CYP-selective inhibitors on N-demethylation were also determined. 3. A single-enzyme Michaelis-Menten model with autoinhibition best fitted CYP2C8*1/*1 HLM (n = 5) and recombinant CYP2C8 kinetic data (median ± SD Ki = 139 ± 61 µM and 149 µM, respectively)...

Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, gemfibrozil reduced the peak plasma concentration (Cmax) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the Cmax and area under the plasma concentration-time curve (AUC0-∞) of N-desmethylimatinib by 56 and 48% (P < 0...

Recent data suggest that the role of CYP3A4 in imatinib metabolism is smaller than presumed. This study aimed to evaluate the quantitative importance of different cytochrome P450 (P450) enzymes in imatinib pharmacokinetics. First, the metabolism of imatinib was investigated using recombinant P450 enzymes and human liver microsomes with P450 isoform-selective inhibitors. Thereafter, an in silico model for imatinib was constructed to perform pharmacokinetic simulations to assess the roles of P450 enzymes in imatinib elimination at clinically used imatinib doses...

BACKGROUND AND PURPOSE: Imatinib, a cytochrome P450 2C8 (CYP2C8) and CYP3A4 substrate, markedly increases plasma concentrations of the CYP3A4/5 substrate simvastatin and reduces hepatic CYP3A4/5 activity in humans. Because competitive inhibition of CYP3A4/5 does not explain these in vivo interactions, we investigated the reversible and time-dependent inhibitory effects of imatinib and its main metabolite N-desmethylimatinib on CYP2C8 and CYP3A4/5 in vitro. EXPERIMENTAL APPROACH: Amodiaquine N-deethylation and midazolam 1'-hydroxylation were used as marker reactions for CYP2C8 and CYP3A4/5 activity...

BACKGROUND AND PURPOSE: Imatinib is a clinically important inhibitor of tyrosine kinases that are dysregulated in chronic myelogenous leukaemia and gastrointestinal stromal tumours. Inter-individual variation in imatinib pharmacokinetics is extensive, and influences drug safety and efficacy. Hepatic cytochrome P450 (CYP) 3A4 has been implicated in imatinib N-demethylation, but the clearance of imatinib decreases during prolonged therapy. CYP3A phenotype correlates with imatinib clearance at the commencement of therapy, but not at steady state...

BACKGROUND: Nilotinib, a second-generation tyrosine kinase inhibitor (TKI) formerly known as AMN107, was approved by the US Food and Drug Administration (FDA) on October 29, 2007, for the treatment of adult patients with chronic-phase (CP) and accelerated-phase (AP) Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) resistant to or intolerant of prior treatment that included imatinib. OBJECTIVE: The purpose of this review was to evaluate the pharmacology, pharmacokinetic properties, and pharmacodynamic properties of nilotinib; results of clinical trials in patients with CML, Ph+ acute lymphoblastic leukemia (ALL), and gastrointestinal stromal tumors (GISTs); and potential drug interactions...