The potent mechanism-based inactivation of CYP2D6 and CYP3A4 with fusidic acid in in vivo bioaccumulation.
Article Details
- CitationCopy to clipboard
Lin XX, Lian GH, Xu Y, Zhao Q, Xiao J, Peng SF, Xiao MF, Ouyang DS, Tan ZR, Wang YC, Peng JB, Zhang W, Chen Y
The potent mechanism-based inactivation of CYP2D6 and CYP3A4 with fusidic acid in in vivo bioaccumulation.
Xenobiotica. 2018 Oct;48(10):999-1005. doi: 10.1080/00498254.2017.1390628. Epub 2017 Nov 10.
- PubMed ID
- 29027845 [ View in PubMed]
- 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 alpha-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 muM FA for 15 min. KI and kinact were found to be 2.87 muM and 0.033 min(-1), respectively, for CYP2D6, while they were 1.95 muM 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Fusidic acid Cytochrome P450 2D6 Protein Humans UnknownSubstrateInhibitorDetails Fusidic acid Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareRivaroxabanFusidic acid The serum concentration of Rivaroxaban can be increased when it is combined with Fusidic acid.