The Antimicrobial Agent Fusidic Acid Inhibits Organic Anion Transporting Polypeptide–Mediated Hepatic Clearance and May Potentiate Statin-Induced Myopathy

摘要

Chronic treatment of methicillin-resistant Staphylococcus aureus strains with the bacteriostatic agent fusidic acid (FA) is frequently associated with myopathy including rhabdomyolysis upon coadministration with statins. Because adverse effects with statins are usually the result of drug–drug interactions, we evaluated the inhibitory effects of FA against human CYP3A4 and clinically relevant drug transporters such as organic anion transporting polypeptides OATP1B1 and OATP1B3, multidrug resistant protein 1, and breast cancer resistance protein, which are involved in the oral absorption and/or systemic clearance of statins including atorvastatin, rosuvastatin, and simvastatin. FA was a weak reversible (IC50 = 295 ± 1.0 μM) and time-dependent (KI = 216 ± 41 μM and kinact = 0.0179 ± 0.001 min?1) inhibitor of CYP3A4-catalyzed midazolam-1′-hydroxylase activity in human liver microsomes. FA demonstrated inhibition of multidrug resistant protein 1–mediated digoxin transport with an IC50 value of 157 ± 1.0 μM and was devoid of breast cancer resistance protein inhibition (IC50 > 500 μM). In contrast, FA showed potent inhibition of OATP1B1- and OATP1B3-specific rosuvastatin transport with IC50 values of 1.59 μM and 2.47 μM, respectively. Furthermore, coadministration of oral rosuvastatin and FA to rats led to an approximately 19.3-fold and 24.6-fold increase in the rosuvastatin maximum plasma concentration and area under the plasma concentration–time curve, respectively, which could be potentially mediated through inhibitory effects of FA on rat Oatp1a4 (IC50 = 2.26 μM) and Oatp1b2 (IC50 = 4.38 μM) transporters, which are responsible for rosuvastatin uptake in rat liver. The potent inhibition of human OATP1B1/OATP1B3 by FA could attenuate hepatic uptake of statins, resulting in increased blood and tissue concentrations, potentially manifesting in musculoskeletal toxicity