TY - JOUR T1 - SORAFENIB AND SUNITINIB, TWO ANTI-CANCER DRUGS, INHIBIT CYP3A4- AND ACTIVATE CY3A5-MEDIATED MIDAZOLAM 1'-HYDROXYLATION JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.110.037853 SP - dmd.110.037853 AU - Minako Sugiyama AU - Ken-ichi Fujita AU - Norie Murayama AU - Yuko Akiyama AU - Hiroshi Yamazaki AU - Yasutsuna Sasaki Y1 - 2011/01/25 UR - http://dmd.aspetjournals.org/content/early/2011/01/25/dmd.110.037853.abstract N2 - 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. 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 around 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. Preincubation period of sorafenib and sunitinib before the midazolam addition in 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 as 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 hetrotropic cooperativity of CYP3A5. ER -