Autoinhibition of CYP3A4 leads to important role of CYP2C8 in imatinib metabolism: variability in CYP2C8 activity may alter plasma concentrations and response.
نویسندگان
چکیده
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. In vitro, CYP2C8 inhibitors and CYP3A4 inhibitors inhibited the depletion of 0.1 µM imatinib by 45 and 80%, respectively, and the formation of the main metabolite of imatinib, N-desmethylimatinib, by >50%. Likewise, recombinant CYP2C8 and CYP3A4 metabolized imatinib extensively, whereas other isoforms had minor effect on imatinib concentrations. In the beginning of imatinib treatment, the fractions of its hepatic clearance mediated by CYP2C8 and CYP3A4 were predicted to approximate 40 and 60%, respectively. During long-term treatment with imatinib 400 mg once or twice daily, up to 65 or 75% of its hepatic elimination was predicted to occur via CYP2C8, and only about 35 or 25% by CYP3A4, due to dose- and time-dependent autoinactivation of CYP3A4 by imatinib. Thus, although CYP2C8 and CYP3A4 are the main enzymes in imatinib metabolism in vitro, in silico predictions indicate that imatinib inhibits its own CYP3A4-mediated metabolism, assigning a key role for CYP2C8. During multiple dosing, pharmacogenetic polymorphisms and drug interactions affecting CYP2C8 activity may cause marked interindividual variation in the exposure and response to imatinib.
منابع مشابه
Autoinhibition of CYP3A4 Leads to Major Role of CYP2C8 in Imatinib Metabolism: Variability in CYP2C8 Activity May Alter Plasma Concentrations and Response
متن کامل
Dmd048017 50..59
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...
متن کاملInvolvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro.
To clarify the oxidative metabolism of methadone (R)- and (S)-enantiomers, the depletion of parent (R)- and (S)-methadone and the formation of racemic 2-ethylidene-1,5-dimethyl-3,3-diphe-nylpyrolidine were studied using human liver microsomes and recombinant cytochrome P450 enzymes. Based on studies with isoform-selective chemical inhibitors and expressed enzymes, CYP3A4 was the predominant enz...
متن کاملPHARMACOKINETIC PROFILE AFTER AMIODARONE HCl INJECTION ADMINISTRATION
P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. The highly variable systemic availability of oral amiodarone may be attributed potentially to large interindividual variability in CYP3A4 activity. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither a...
متن کاملGemfibrozil inhibits CYP2C8-mediated cerivastatin metabolism in human liver microsomes.
To explore the mechanism of the interaction between gemfibrozil and cerivastatin, the enzyme mapping of the oxidative metabolism of cerivastatin and the effect of gemfibrozil on cerivastatin metabolism were studied using human liver microsomes and expressed cytochrome p450 (p450) CYP2C8 and 3A4 isoforms. Based on studies with isoform-selective chemical inhibitors and expressed enzymes, CYP2C8 a...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Drug metabolism and disposition: the biological fate of chemicals
دوره 41 1 شماره
صفحات -
تاریخ انتشار 2013