title: The Antimicrobial Agent Fusidic Acid Inhibits Organic Anion Transporting Polypeptide-Mediated Hepatic Clearance and May Potentiate Statin-Induced Myopathy.
abstract: 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.
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Groton, Connecticut (H.E., R.J.S., C.J.R., J.L., S.L., M.V.V., L.D., B.F., M.W.); and Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Cambridge MA (A.S.K.).
authors.forename: Heather
authors.initials: H
authors.lastname: Eng
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Groton, Connecticut (H.E., R.J.S., C.J.R., J.L., S.L., M.V.V., L.D., B.F., M.W.); and Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Cambridge MA (A.S.K.).
authors.forename: Renato J
authors.initials: RJ
authors.lastname: Scialis
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Groton, Connecticut (H.E., R.J.S., C.J.R., J.L., S.L., M.V.V., L.D., B.F., M.W.); and Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Cambridge MA (A.S.K.).
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Rotter
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Groton, Connecticut (H.E., R.J.S., C.J.R., J.L., S.L., M.V.V., L.D., B.F., M.W.); and Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Cambridge MA (A.S.K.).
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Groton, Connecticut (H.E., R.J.S., C.J.R., J.L., S.L., M.V.V., L.D., B.F., M.W.); and Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Cambridge MA (A.S.K.).
authors.forename: Sarah
authors.initials: S
authors.lastname: Lazzaro
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Groton, Connecticut (H.E., R.J.S., C.J.R., J.L., S.L., M.V.V., L.D., B.F., M.W.); and Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Cambridge MA (A.S.K.).
authors.forename: Manthena V
authors.initials: MV
authors.lastname: Varma
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Groton, Connecticut (H.E., R.J.S., C.J.R., J.L., S.L., M.V.V., L.D., B.F., M.W.); and Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Cambridge MA (A.S.K.).
authors.forename: Li
authors.initials: L
authors.lastname: Di
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Groton, Connecticut (H.E., R.J.S., C.J.R., J.L., S.L., M.V.V., L.D., B.F., M.W.); and Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Cambridge MA (A.S.K.).
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Groton, Connecticut (H.E., R.J.S., C.J.R., J.L., S.L., M.V.V., L.D., B.F., M.W.); and Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Cambridge MA (A.S.K.).
authors.forename: Michael
authors.initials: M
authors.lastname: West
authors.affiliation: Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Groton, Connecticut (H.E., R.J.S., C.J.R., J.L., S.L., M.V.V., L.D., B.F., M.W.); and Pharmacokinetics, Pharmacodynamics, and Metabolism Department-New Chemical Entities, Pfizer Inc., Cambridge MA (A.S.K.) amit.kalgutkar@pfizer.com.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D001692:Biological Transport; D002460:Cell Line; D004285:Dogs; D005260:Female; D005672:Fusidic Acid / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027361:Organic Anion Transporters; D010455:Peptides; D005672:Fusidic Acid