Effects of CYP3A inhibitors ketoconazole, voriconazole, and itraconazole on the pharmacokinetics of sunitinib and its main metabolite in rats

• Published in: Chemico-biological interactions Vol. 338; p. 109426
• Main Authors: Wang, Jun, Cui, Xiao, Cheng, Chen, Wang, Yi, Sun, Wei, Huang, Cheng-ke, Chen, Rui-jie, Wang, Zhe
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.04.2021
• Subjects: Administration, Oral; Animals; CYP3A; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Drug-drug interactions; Equipotent metabolite; Itraconazole - pharmacology; Ketoconazole - pharmacology; Male; Pharmacokinetics; Rats; Rats, Sprague-Dawley; Sunitinib; Sunitinib - administration & dosage; Sunitinib - pharmacokinetics; Voriconazole - pharmacology; CYP3A; Sunitinib; Equipotent metabolite; Drug-drug interactions; Pharmacokinetics
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2021.109426

Sunitinib is a small molecule inhibitor of multiple receptor tyrosine kinases such as platelet derived growth factor receptor, vascular endothelial growth factor receptor, kit receptor and other receptors. The US Food and Drug Administration (FDA) has approved sunitinib for the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors. It has been reported that sunitinib was mainly metabolized by CYP3A but its pharmacokinetic interactions have not been revealed. In this study, we investigated whether CYP3A inhibitors (ketoconazole, voriconazole, and itraconazole) could influence the pharmacokinetics of sunitinib and its equipotent metabolite N-desethyl sunitinib in a drug-drug interaction study in Sprague Dawley (SD) rats. The results showed that ketoconazole and voriconazole significantly increased the exposure of sunitinib, decreased the exposure of N-desethyl sunitinib, and inhibited the metabolism of sunitinib in rats. However, itraconazole showed only a weak effect on pharmacokinetics and metabolism. Coadministration of sunitinib with ketoconazole and voriconazole should be avoided if possible or if not, there should be therapeutic drug monitoring of the levels of sunitinib and N-desethyl sunitinib. Therefore, drug-drug interaction should be considered when sunitinib is administered in conjunction with CYP3A inhibitors, which might lead to toxicity. •CYP3A inhibitors altered the pharmacokinetics of sunitinib and its metabolite in rat.•Azole antifungal agents had different inhibitory effect on sunitinib metabolism.•Itraconazloe had the weakest effect on the metabolism of sunitinib.