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

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The Antimicrobial Agent Fusidic Acid Inhibits Organic Anion Transporting Polypeptide–Mediated Hepatic Clearance and May Potentiate Statin-Induced Myopathy 1521-009X/44/5/692–699$25.00 http://dx.doi.org/10.1124/dmd.115.067447 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 44:692–699, May 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics The Antimicrobial Agent Fusidic Acid Inhibits Organic Anion Transporting Polypeptide–Mediated Hepatic Clearance and May Potentiate Statin-Induced Myopathy Heather Eng, Renato J. Scialis, Charles J. Rotter, Jian Lin, Sarah Lazzaro, Manthena V. Varma, Li Di, Bo Feng, Michael West, and Amit S. Kalgutkar 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.) Received September 28, 2015; accepted February 12, 2016 Downloaded from ABSTRACT Chronic treatment of methicillin-resistant Staphylococcus aureus with an IC50 value of 157 6 1.0 mM and was devoid of breast strains with the bacteriostatic agent fusidic acid (FA) is frequently cancer resistance protein inhibition (IC50 > 500 mM).Incontrast, associated with myopathy including rhabdomyolysis upon coad- FA showed potent inhibition of OATP1B1- and OATP1B3-specific ministration with statins. Because adverse effects with statins are rosuvastatin transport with IC50 values of 1.59 mM and 2.47 mM, usually the result of drug–drug interactions, we evaluated the respectively. Furthermore, coadministration of oral rosuvastatin dmd.aspetjournals.org inhibitory effects of FA against human CYP3A4 and clinically relevant and FA to rats led to an approximately 19.3-fold and 24.6-fold drug transporters such as organic anion transporting polypeptides increase in the rosuvastatin maximum plasma concentration and OATP1B1 and OATP1B3, multidrug resistant protein 1, and breast area under the plasma concentration–time curve, respectively, cancer resistance protein, which are involved in the oral absorp- which could be potentially mediated through inhibitory effects of tion and/or systemic clearance of statins including atorvastatin, FA on rat Oatp1a4 (IC50 =2.26mM) and Oatp1b2 (IC50 =4.38mM) rosuvastatin, and simvastatin. FA was a weak reversible (IC50 = transporters, which are responsible for rosuvastatin uptake in rat 295 6 1.0 mM) and time-dependent (K = 216 6 41 mM and k = liver. The potent inhibition of human OATP1B1/OATP1B3 by FA I inact at ASPET Journals on September 27, 2021 0.0179 6 0.001 min21) inhibitor of CYP3A4-catalyzed midazolam-19- could attenuate hepatic uptake of statins, resulting in increased hydroxylase activity in human liver microsomes. FA demonstrated blood and tissue concentrations, potentially manifesting in mus- inhibition of multidrug resistant protein 1–mediated digoxin transport culoskeletal toxicity. Introduction Saeed and Azam, 2009; Collidge et al., 2010; Magee et al., 2010; Fusidic acid (FA; Fig. 1) is an orally active bacteriostatic antibiotic Teckchandani et al., 2010; Kearney et al., 2012; Gabignon et al., 2013), with wide clinical usage in Europe and Australasia for the treatment of and more recently, rosuvastatin (Cowan et al., 2013). The package insert methicillin-resistant Staphylococcus aureus and, more recently, multi- for sodium fusidate (Fusidin tablets) was also recently amended with resistant Staphylococcus aureus strains (Vanderhelst et al., 2013; Hall et al., additional warnings to reflect the adverse musculoskeletal findings 2015). Furthermore, in countries where FA is available, chronic oral therapy (https://www.medicines.org.uk/emc/medicine/2448). with FA is routinely used in the treatment of Staphylococcus-mediated The precise cause(s) of myopathy including rhabdomyolysis remains prosthetic joint infections among the elderly population (Aboltins et al., unclear. The FA package insert and the medical literature suggests 2007; Wang et al., 2012). The widespread clinical use of FA in suppressive inhibition of CYP3A4 by FA as a likely mechanism of muscular side antibiotic therapy is also associated with several cases of life-threatening effects (Burtenshaw et al., 2008; Collidge et al., 2010; Teckchandani rhabdomyolysis (with fatalities) upon coadministration with the et al., 2010; Kearney et al., 2012), since CYP3A4 is principally 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, atorvastatin responsible for the metabolic clearance of atorvastatin and simvastatin and simvastatin (Wenisch et al., 2000; Yuen and McGarity, 2003; in humans (Lennernäs, 2003; Elsby et al., 2012). However, it is now Burtenshaw et al., 2008; O’Mahony et al., 2008; Herring et al., 2009; widely recognized that the systemic clearance of statins such as atorvastatin, simvastatin, and rosuvastatin is predominantly determined This research was supported by Pfizer, Inc. by the hepatic uptake mediated by organic anion transporting polypep- dx.doi.org/10.1124/dmd.115.067447. tides (OATPs; OATP1B1, OATP1B3, and OATP2B1) (Neuvonen et al., ABBREVIATIONS: 95% CI, 95% confidence interval; AUC, area under the plasma concentration-time curve; CP-628374, (2E)-3-(4- {[(2S,3S,4S,5R)-5-{(1E)-N-[(3-chloro-2,6-difluorobenzyl)oxy]ethanimidoyl}-3,4-dihydroxytetrahydrofuran-2-yl]oxy}-3-hydroxyphenyl)-2-methyl-N- [(3aS,4R,5R,6S,7R,7aR)-4,6,7-trihydroxyhexahydro-1,3-benzodioxol-5-yl]prop-2-enamide; DDI, drug–drug interaction; ER, efflux ratio; FA, fusidic acid; Fa, fraction of the oral dose absorbed; fu, fraction unbound; HBSS, Hanks’ balanced salt solution; HEK, human embryonic kidney; HPLC, high-performance liquid chromatography; LC-MS/MS, liquid chromatography–tandem mass spectrometry; MDCKII, Madin– Darby canine kidney II; MDCKII-LE, Madin–Darby canine kidney–low efflux; MRM, multiple reaction monitoring; OATP, organic anion transporting polypeptide; P450, cytochrome P450; t1/2, half-life; TDI, time-dependent inhibition; Tmax, time of first occurrence of Cmax. 692 Drug–Drug Interaction between Statins and Fusidic Acid 693 CYP3A4 Inhibition Studies. Reversible inhibition of human CYP3A4 by FA was evaluated in pooled human liver microsomes (protein concentration = 0.05 mg/ml) in the presence of NADPH (1.3 mM) in 100 mM potassium phosphate buffer, pH 7.4, containing 3.3 mM MgCl2 at 37°C open to air. The incubation volume was 0.2 ml and four replicates were included per FA concentration. Incubation mixtures contained FA at concentrations ranging from 0.1 to 1000 mM and midazolam (4 mM) as the probe CYP3A4 substrate. At the end of the incubation period (5 minutes), acetonitrile containing 19-(d4)- hydroxymidazolam (0.1 mg/ml) as internal standard was added, and the mixture was centrifuged (2000 Â g, 5 minutes at room temperature). The concentration of midazolam used in the assay approximated its KM value that had been previously determined, and the incubation time was selected based on previous determi- nations of reaction velocity linearity (Walsky and Obach, 2004). The supernatant Fig. 1. Structure of FA. was mixed with an equal volume of water containing 0.2% formic acid and was then analyzed by liquid chromatography–tandem mass spectrometry (LC-MS/ MS) for 19-hydroxymidazolam using validated bioanalytical conditions estab- 2006; Kitamura et al., 2008; Zamek-Gliszczynski et al., 2009; König lished previously (Walsky and Obach, 2004). Formation of 19-hydroxymidazolam et al., 2013). According to the extended clearance classification system was quantitated using Analyst software (version 1.6; Sciex, Framingham, MA). 2 (Varma et al., 2015), statins fall into class 1B and 3B, wherein the Standard curve regression used linear regression with 1/x weighting. Resulting Downloaded from OATP1B1-mediated hepatic uptake is the rate-determining step in their 19-hydroxymidazolam concentrations were normalized to concentrations mea- systemic clearance, although class 1B compounds (e.g., atorvastatin and sured in solvent controls. The IC50 value was calculated with GraphPad software simvastatin) are ultimately eliminated from the body as metabolites and (version 6; GraphPad Software, San Diego, CA) using the log(inhibitor) versus class 3B statins (e.g., rosuvastatin) are eliminated unchanged in feces via normalized response equation assuming a Hill slope of 21.0; automatic outlier biliary excretion. Several drug–drug interaction (DDI) studies indicate determination was enabled and no curve fitting restraints were included. that OATPs inhibitors such as rifampicin and cyclosporine A exhibit a To examine the ability of FA to act as a time- and concentration-dependent inhibitor of human CYP3A4, incubations were carried out with seven FA dmd.aspetjournals.org profound effect on the plasma exposure of statins (Hermann et al., 2004; concentrations in duplicate. Inactivation kinetic experiments have been de- Lau et al., 2007). For instance, in a microdose study, the area under the scribed previously (Ghanbari et al., 2006; Obach et al., 2007; Polasek and plasma concentration-time curve (AUC) of atorvastatin was shown to be Miners, 2007). Human liver microsomes (0.3 mg/ml), MgCl2 (3.3 mM), and markedly increased upon coadministration with a single oral rifampicin NADPH (1.3 mM) in potassium phosphate buffer (100 mM, pH 7.4) were dose, but not in the presence of an intravenous dose of itraconazole, a prewarmed in a dry heat bath at 37°C for 5 minutes. Incubation was initiated with potent CYP3A4 inhibitor, indicating that OATP-mediated uptake in the addition of inhibitor or control solvent (2 ml, final incubation volume 0.2 ml). the liver is the rate-determining
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