Fusidic Acid Inhibits Hepatic Transporters and Metabolic Enzymes: Potential Cause of Clinical Drug-Drug Interaction Observed with Statin Coadministration.
Antimicrob Agents Chemother
; 60(10): 5986-94, 2016 10.
Article
en En
| MEDLINE
| ID: mdl-27458210
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], â¼50 to 110 µM) and OATP1B1-mediated uptake (IC50, â¼4 to 35 µM) 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 â¼4 mM, and the maximum total or unbound concentration in the inlet to the liver was reported to be up to 223 µM or 11 µM, respectively, upon multiple dosing). Similarly, FA inhibited metabolism of statins in human liver microsomes (IC50, â¼17 to 195 µM). 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.
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1
Bases de datos:
MEDLINE
Asunto principal:
Microsomas Hepáticos
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Inhibidores de Hidroximetilglutaril-CoA Reductasas
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Hepatocitos
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Inhibidores Enzimáticos del Citocromo P-450
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Ácido Fusídico
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Antibacterianos
Límite:
Animals
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Humans
Idioma:
En
Revista:
Antimicrob Agents Chemother
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos