科研之友
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摘要
Dabrafenib is a drug used to treat cancers, and zidovudine (AZT) is a clinical drug to treat HIV infection. This study aims to investigate the potential drug-drug interaction between dabrafenib and AZT through determining the inhibition of dabrafenib towards the glucuronidation metabolism of AZT. Furthermore, the inhibition of dabrafenib on the activity of AZT glucuronidation drug-metabolizing enzyme (DME) UDP-glucuronosyltransferase (UGT) 2B7 was evaluated to explain the potential mechanism. Dabrafenib 100 mu M inhibited 85% activity of glucuronidation of AZT. Furthermore, the inhibition of dabrafenib on the activity of UGT2B7 was investigated, and the results showed that 93% activity of UGT2B7 was inhibited by 100 mu M of dabrafenib. Concentration-dependent inhibition of dabrafenib on the activity of UGT2B7 was demonstrated, and the half inhibition concentration (IC50) was calculated to be approximately 10 mu M. Furthermore, inhibition kinetic type was determined using the concentrations covering the Km value and IC50 values. In the Lineweaver-Burk plot, the intersection point was located in the vertical axis, indicating the competitive inhibition of dabrafenib on the activity of UGT2B7. In the second plot, the slopes of the lines were drawn versus the concentrations of dabrafenib, and the linear fitting equation was calculated to be y = 28.4x + 735.7. Based on this equation, the inhibition kinetic parameter (Ki) was determined to be 25.9 mu M. All these results indicated the potential dabrafenib-AZT interaction in the clinic.
