Abstract
Sorafenib and sunitinib are novel small-molecule molecularly targeted anticancer drugs that inhibit multiple tyrosine kinases. These medicines have shown survival benefits in advanced renal cell carcinomas as well as in advanced hepatocellular carcinomas and gastrointestinal stromal tumors, respectively. The effects of sorafenib and sunitinib on midazolam 1′-hydroxylation catalyzed by human CYP3A4 or CYP3A5 were investigated. Sorafenib and sunitinib inhibited metabolic reactions catalyzed by recombinant CYP3A4. Midazolam hydroxylation was also inhibited in human liver microsomes harboring the CYP3A5*3/*3 genotype (poor CYP3A5 expressor). In contrast, midazolam 1′-hydroxylation catalyzed by recombinant CYP3A5 was enhanced by the coexistence of sorafenib or sunitinib in a concentration-dependent manner, with saturation occurring at approximately 10 μM. Midazolam hydroxylation was also enhanced in human liver microsomal samples harboring the CYP3A5*1/*1 genotype (extensive CYP3A5 expressor). Sorafenib N-oxidation and sunitinib N-deethylation, the primary routes of metabolism, were predominantly catalyzed by CYP3A4 but not by CYP3A5. The preincubation period of sorafenib and sunitinib before the midazolam addition in the reaction mixture did not affect the enhancement of CYP3A5-catalyzed midazolam hydroxylation, indicating that the enhancement was caused by parent sorafenib and sunitinib. Docking studies with a CYP3A5 homology model based on the structure of CYP3A4 revealed that midazolam closely docked to the heme of CYP3A5 compared with sorafenib or sunitinib, suggesting that these anticancer drugs act as enhancers, not as substrates. Our results thus showed that sorafenib and sunitinib activated midazolam 1′-hydroxylation by CYP3A5 but inhibited that by CYP3A4. Unexpected drug interactions involving sorafenib and sunitinib might occur via heterotropic cooperativity of CYP3A5.
Footnotes
This study was supported by in part by the Ministry of Health, Labour and Welfare of Japan [Grant-in-Aid for Cancer Research 21S-8-1]; the Ministry of Education, Culture, Sports, Science and Technology [Grant-in-aid for “Support Project of Strategic Research Center in Private Universities”] (to Saitama Medical University Research Center for Genomic Medicine); and the Ministry of Education, Culture, Sports, Science and Technology [Grant-in-Aid 19-8 for High Technology Research Centre Project] (to Showa Pharmaceutical University).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.037853.
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ABBREVIATIONS:
- P450
- cytochrome P450
- FDA
- U.S. Food and Drug Administration
- HLM
- human liver microsomes
- HPLC
- high-performance liquid chromatography.
- Received December 17, 2010.
- Accepted January 25, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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