PT  - JOURNAL ARTICLE
AU  - Yedong Wang
AU  - Meiyu Wang
AU  - Huixin Qi
AU  - Peichen Pan
AU  - Tingjun Hou
AU  - Jiajun Li
AU  - Guangzhao He
AU  - Hongjian Zhang
TI  - Pathway-Dependent Inhibition of Paclitaxel Hydroxylation by Kinase Inhibitors and Assessment of Drug–Drug Interaction Potentials
AID  - 10.1124/dmd.113.053793
DP  - 2014 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 782--795
VI  - 42
IP  - 4
4099  - http://dmd.aspetjournals.org/content/42/4/782.short
4100  - http://dmd.aspetjournals.org/content/42/4/782.full
SO  - Drug Metab Dispos2014 Apr 01; 42
AB  - Paclitaxel is often used in combination with small molecule kinase inhibitors to enhance antitumor efficacy against various malignancies. Because paclitaxel is metabolized by CYP2C8 and CYP3A4, the possibility of drug–drug interactions mediated by enzyme inhibition may exist between the combining agents. In the present study, a total of 12 kinase inhibitors were evaluated for inhibitory potency in human liver microsomes by monitoring the formation of CYP2C8 and CYP3A4 metabolites simultaneously. For reversible inhibition, nilotinib was found to be the most potent inhibitor against both CYP2C8 and CYP3A4, and the inhibition potency could be explained by strong hydrogen binding based on molecular docking simulations and type II binding based on spectral analysis. Comparison of Ki values revealed that the CYP2C8 pathway was more sensitive toward some kinase inhibitors (such as axitinib), while the CYP3A4 pathway was preferentially inhibited by others (such as bosutinib). Pathway-dependent inactivation (time-dependent inhibition) was also observed for a number of kinase inhibitors against CYP3A4 but not CYP2C8. Further studies showed that axitinib had a KI of 0.93 μM and kinact of 0.0137 min−1, and the observed inactivation toward CYP3A4 was probably due to the formation of reactive intermediate(s). Using a static model, a reasonably accurate prediction of drug–drug interactions was achieved by incorporating parallel pathways and hepatic extraction ratio. The present results suggest that potent and pathway-dependent inhibition of CYP2C8 and/or CYP3A4 pathways by kinase inhibitors may alter the ratio of paclitaxel metabolites in vivo, and that such changes can be clinically relevant as differential metabolism has been linked to paclitaxel-induced neurotoxicity in cancer patients.