Autoinhibition of CYP3A4 Leads to Important Role of CYP2C8 in Imatinib Metabolism: Variability in CYP2C8 Activity May Alter Plasma Concentrations and Response

Abstract

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 mM 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 timedependent 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.

Imatinib and Norimatinib Plasma Levels Analyses of Chronic Myeloid Leukemia Patients

“…Nevetheless, norimatinib transformation was 12.20%, within the expected range. 5,6,10 He was on concomitant losartan treatment at the date of sample collection. Losartan is expected to increase exposure to imatinib.…”

“…Therefore, the analysis was performed in accordance with the 10-30% interval discussed in various studies. 5,6,10 Statistical analysis resulted in a mean age of 46.975±13.150 and 4.292±3.156 years of mean period of treatment. Mean plasma imatinib and norimatinib levels were 4.038±1.290 ppm and 1.150±0.733 ppm, respectively.…”

“…[1][2][3] Imatinib is a targeted, potent and competitive TKI; it is designed to selectively interfere with key signal transduction pathways. [4][5][6] It performs its therapeutic activity on CML by competitive inhibition at the ATP-binding site. 4,7,8 This way, tyrosine kinase phosphorylation of proteins acting in Bcr-Abl signal transduction is inhibited.…”

“…10 It is considered to be a clinically successful molecule due to its effectiveness and high tolerance profiles in CML patients. 6 Imatinib is administered orally as first line therapy to adult, chronic phase CML patients at daily doses of 400 mg, 600 mg or even 800 mg. 7,9 Dosage titration is usually planned according to the hematological responses which are monitored in the various phases of the disease and to the adverse reactions which are related to the patient and treatment regime. Imatinib yields close concentration/effect levels as regards to other cytotoxic agents.…”

“…7 Clinical studies show that the optimal response is attained at 1000 ng/ml of imatinib plasma concentration and is maintained at concentrations above this threshold. 6,10 Imatinib metabolism depends primarily on the presence of cytochrome P450 enzymes, whose active metabolite is norimatinib. Norimatinib accumulation in plasma is 10-30% of imatinib.…”