Pathway-dependent inhibition of paclitaxel hydroxylation by kinase inhibitors and assessment of drug-drug interaction potentials.
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 K(i) 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 K(I) of 0.93 μM and k(inact) 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.
College of Pharmaceutical Sciences (Y.W., M.W., H.Q., T.H., J.L., G.H., H.Z.), Institute of Functional Nano and Soft Materials, and Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices (P.P., T.H.), Soochow University, Suzhou, People's Republic of China.
Yedong
Y
Wang
Meiyu
M
Wang
Huixin
H
Qi
Peichen
P
Pan
Tingjun
T
Hou
Jiajun
J
Li
Guangzhao
G
He
Hongjian
H
Zhang
D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism* / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D062105:Molecular Docking Simulation; D017239:Paclitaxel / Q000378:metabolism* / Q000493:pharmacokinetics; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
D000972:Antineoplastic Agents, Phytogenic; D047428:Protein Kinase Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel