Anti-Cancer Drug Vemurafenib Showed Strong Inhibition on the Activity of Drug-Metabolizing Enzymes

Melanoma is a malignant tumour of melanocytes, and vemurafenib is an efficient drug clinically used to treat melanoma under the trade name Zelboraf. This study aims to determine the inhibition potential of vemurafenib on the activity of carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2). In vitro human liver microsomes (HLMs)-catalyzed hydrolysis metabolism of 2-(2-benzoyl-3-methoxyphenyl) benzothiazole (BMBT) to form its hydrolysis metabolite 2-(2-hydroxy-3-methoxyphenyl) benzothiazole (HMBT) was used to investigate the inhibition of vemurafenib on the activity of CES1, and in vitro human liver microsomes (HLMs)-catalyzed hydrolysis metabolism of fluorescein diacetate (FD) to fluorescein was used to investigate the inhibition of vemurafenib on the activity of CES2. The results showed that 100 mu M of vemurafenib did not show significant inhibition on the activity of CES1. In the contrast, 100 mu M of vemurafenib showed significant inhibition on the activity of CES2 (p < 0.001). For the inhibition of vemurafenib on the activity of CES2, the half concentration inhibiting 50% activity of CES2 was calculated, and the results showed that the IC50 value of vemurafenib's inhibition on CES2 was calculated to be 25.1 mu M. In conclusion, drug-drug interaction might exist between vemurafenib and clinical drugs mainly undergoing CES2-catalyzed hydrolysis metabolism.