The potent mechanism-based inactivation of CYP2D6 and CYP3A4 with fusidic acid in in vivo bioaccumulation |
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| Authors: | Xiu-Xian Lin Guang-Hui Lian Ying Xu Qing Zhao Jian Xiao Shi-Fang Peng |
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| Institution: | 1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China,;2. Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China,;3. Department of gastroenterology, Xiangya Hospital, Central South University, Changsha, Hunan, China,;4. Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China,;5. Department of Hepatology and Infectious Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, China, and;6. Health Management Center, Xiangya Hospital, Central South University, Changsha, Hunan, China |
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| Abstract: | 1.?The accumulation of fusidic acid (FA) after multiple doses of FA has been reported on in previous studies but the related mechanisms have not been clarified fully. In the present study, we explain the mechanisms related to the mechanism-based inactivation of CYP2D6 and CYP3A4.2.?The irreversible inhibitory effects of FA on CYP2D6 and CYP3A4 were examined via a series of experiments, including: (a) time-, concentration- and NADPH-dependent inactivation, (b) substrate protection in enzyme inactivation and (c) partition ratio with recombinant human CYP enzymes. Metoprolol α-hydroxylation and midazolam 1′-hydroxylation were used as marker reactions for CYP2D6 and CYP3A4 activities, and HPLC-MS/MS measurement was also utilised.3.?FA caused to the time- and concentration-dependent inactivation of CYP2D6 and CYP3A4. About 55.8% of the activity of CYP2D6 and 75.8% of the activity of CYP3A4 were suppressed after incubation with 10?μM FA for 15?min. KI and kinact were found to be 2.87?μM and 0.033?min?1, respectively, for CYP2D6, while they were 1.95?μM and 0.029?min?1, respectively, for CYP3A4. Inhibition of CYP2D6 and CYP3A4 activity was found to require the presence of NADPH. Substrates of CYP2D6 and CYP3A4 showed that the enzymes were protected against the inactivation induced by FA. The estimated partition ratio for the inactivation was 7 for CYP2D6 and 12 for CYP3A4.4.?FA is a potent mechanism-based inhibitor of CYP2D6 and CYP3A4, which may explain the accumulation of FA in vivo. |
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| Keywords: | Accumulation CYP3A4 CYP2D6 fusidic acid mechanism-based inactivation |
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