Abstract
Imatinib is a kinase inhibitor used in the treatment of chronic myeloid leukemia and other cancers. Although its pharmacokinetics is generally predictable, substantial interindividual variability in clearance and exposure remains. In this study, we investigated the impact of cytochrome P450 (P450) enzymes CYP2C8, CYP3A4, and CYP3A5 phenotypes and genotypes on imatinib metabolism using both human liver microsomes (HLMs) and primary human hepatocytes (PHHs). Imatinib clearance and N-desmethyl imatinib formation were quantified by liquid chromatography-tandem mass spectrometry and correlated with enzyme activity, protein concentration, and compared by genotype groups. In single-donor HLMs (n = 21), imatinib clearance varied 45-fold between donors and was strongly associated with CYP2C8 (r = 0.91) and CYP3A (r = 0.90) protein concentrations and CYP2C8 (r = 0.66) and CYP3A (r = 0.86) enzyme activities. A multiple linear regression model identified CYP3A activity and biological sex as significant predictors of imatinib clearance (adjusted R(2) = 0.90, P < .0001). In PHH (n = 14), imatinib clearance varied 10-fold and was significantly correlated with CYP2C8 activity and protein concentration, but not with CYP3A activity. CYP2C8∗3 carriers had significantly lower clearance than ∗1/∗1 donors (P = .012). N-Desmethyl imatinib formation was consistently associated with both CYP2C8 and CYP3A protein concentration and enzyme activity in HLM and PHH. These findings provide further insight into the enzymes driving imatinib metabolism and highlight the relevance of CYP2C8 and CYP3A variability to interindividual differences in drug disposition. These results support the integration of enzyme phenotyping into predictive models to inform imatinib precision dosing approaches. SIGNIFICANCE STATEMENT: This study highlights the influence of CYP2C8 and CYP3A enzymes on interindividual variability in imatinib metabolism in human liver microsomes and primary human hepatocytes. Our findings provide evidence that CYP2C8 phenotypic measures (enzyme activity and protein concentration) are effective in predicting imatinib metabolism in vitro in primary human hepatocytes. Future studies are warranted to examine how preemptive testing of P450 parameters, such as phenotypes and genotypes, in patients before drug administration could aid in therapy optimization and reduction of drug toxicities.