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Research ArticleArticle

Pathway-Dependent Inhibition of Paclitaxel Hydroxylation by Kinase Inhibitors and Assessment of Drug–Drug Interaction Potentials

Yedong Wang, Meiyu Wang, Huixin Qi, Peichen Pan, Tingjun Hou, Jiajun Li, Guangzhao He and Hongjian Zhang
Drug Metabolism and Disposition April 2014, 42 (4) 782-795; DOI: https://doi.org/10.1124/dmd.113.053793
Yedong Wang
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
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Meiyu Wang
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
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Huixin Qi
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
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Peichen Pan
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
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Tingjun Hou
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
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Jiajun Li
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
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Guangzhao He
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
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Hongjian Zhang
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
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Abstract

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.

Footnotes

    • Received July 19, 2013.
    • Accepted January 29, 2014.
  • This work was supported by a grant from Soochow University, Suzhou, People’s Republic of China [Grant Q413200711].

  • dx.doi.org/10.1124/dmd.113.053793.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Research ArticleArticle

Pathway-Dependent Inhibition of Paclitaxel Hydroxylation

Yedong Wang, Meiyu Wang, Huixin Qi, Peichen Pan, Tingjun Hou, Jiajun Li, Guangzhao He and Hongjian Zhang
Drug Metabolism and Disposition April 1, 2014, 42 (4) 782-795; DOI: https://doi.org/10.1124/dmd.113.053793

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Research ArticleArticle

Pathway-Dependent Inhibition of Paclitaxel Hydroxylation

Yedong Wang, Meiyu Wang, Huixin Qi, Peichen Pan, Tingjun Hou, Jiajun Li, Guangzhao He and Hongjian Zhang
Drug Metabolism and Disposition April 1, 2014, 42 (4) 782-795; DOI: https://doi.org/10.1124/dmd.113.053793
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