Fusidic Acid Inhibits Hepatic Transporters and Metabolic Enzymes: Potential Cause of Clinical Drug-Drug Interaction Observed with Statin Coadministration.
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Gupta A, Harris JJ, Lin J, Bulgarelli JP, Birmingham BK, Grimm SW
Fusidic Acid Inhibits Hepatic Transporters and Metabolic Enzymes: Potential Cause of Clinical Drug-Drug Interaction Observed with Statin Coadministration.
Antimicrob Agents Chemother. 2016 Sep 23;60(10):5986-94. doi: 10.1128/AAC.01335-16. Print 2016 Oct.
- PubMed ID
- 27458210 [ View in PubMed]
- Abstract
Fusidic acid (FA), which was approved in the 1960s in many European and Asian countries, has gained renewed interest due to its continued effectiveness against methicillin-resistant Staphylococcus aureus As rhabdomyolysis has been reported upon coadministration of FA with statins, we aimed to elucidate the underlying molecular mechanisms that contribute to FA-statin drug-drug interactions. Because of the association between rhabdomyolysis and increased exposure to statins, we investigated if cytochrome P450 (CYP) enzymes and transporters involved in the disposition of various statins are inhibited by FA. FA was found to inhibit BCRP and OATP1B1 but not P-gp. In overexpressing cell systems, FA inhibited BCRP-mediated efflux (50% inhibitory concentration [IC50], approximately 50 to 110 muM) and OATP1B1-mediated uptake (IC50, approximately 4 to 35 muM) of statins at clinically relevant concentrations achievable in the intestine and liver (based on a 550-mg oral dose of FA, the expected maximum theoretical gastrointestinal concentration is approximately 4 mM, and the maximum total or unbound concentration in the inlet to the liver was reported to be up to 223 muM or 11 muM, respectively, upon multiple dosing). Similarly, FA inhibited metabolism of statins in human liver microsomes (IC50, approximately 17 to 195 muM). These data suggest that FA inhibits at least 3 major dispositional pathways (BCRP, OATP1B1, and CYP3A) and thus affects the clearance of several statins. We confirmed that FA is eliminated via phase 1 metabolism (primarily via CYP3A); however, there is also some phase 2 metabolism (mediated primarily by UGT1A1). Taken together, these data provide evidence for molecular mechanisms that may explain the occurrence of rhabdomyolysis when FA is administered with statins.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Fusidic acid Cytochrome P450 3A4 Protein Humans UnknownSubstrateInhibitorDetails Fusidic acid UDP-glucuronosyltransferase 1-1 Protein Humans UnknownSubstrateDetails - Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Fusidic acid ATP-binding cassette sub-family G member 2 Protein Humans UnknownInhibitorDetails Fusidic acid Solute carrier organic anion transporter family member 1B1 Protein Humans UnknownNot Available Details - 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.