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 ± 1.0μM) and time-dependent (KI= 216 ± 41μM 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 ± 1.0μM and was devoid of
breast cancer resistance
protein inhibition (IC50> 500μM). In contrast, FA showed potent inhibition of OATP1B1- and OATP1B3-specific
rosuvastatin transport with IC50 values of 1.59μM and 2.47μM, 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= 2.26μM) and Oatp1b2 (IC50= 4.38μM) 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.