Rhabdomyolysis following co-prescription of fusidic acid and atorvastatin

Teckchandani, S; Robertson, Sarah; Almond, A; Donaldson, Kirsteen; Isles, Christopher

doi:10.4997/jrcpe.2010.108

Cited by 18 publications

(11 citation statements)

References 22 publications

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“…The FA package insert and the medical literature suggests inhibition of CYP3A4 by FA as a likely mechanism of muscular side effects (Burtenshaw et al, 2008;Collidge et al, 2010;Teckchandani et al, 2010;Kearney et al, 2012), since CYP3A4 is principally responsible for the metabolic clearance of atorvastatin and simvastatin in humans (Lennernäs, 2003;Elsby et al, 2012). However, it is now widely recognized that the systemic clearance of statins such as atorvastatin, simvastatin, and rosuvastatin is predominantly determined by the hepatic uptake mediated by organic anion transporting polypeptides (OATPs; OATP1B1, OATP1B3, and OATP2B1) (Neuvonen et al, 2006;Kitamura et al, 2008;Zamek-Gliszczynski et al, 2009;König et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, in countries where FA is available, chronic oral therapy with FA is routinely used in the treatment of Staphylococcus-mediated prosthetic joint infections among the elderly population (Aboltins et al, 2007;Wang et al, 2012). The widespread clinical use of FA in suppressive antibiotic therapy is also associated with several cases of life-threatening rhabdomyolysis (with fatalities) upon coadministration with the 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, atorvastatin and simvastatin (Wenisch et al, 2000;Yuen and McGarity, 2003;Burtenshaw et al, 2008;O'Mahony et al, 2008;Herring et al, 2009;Saeed and Azam, 2009;Collidge et al, 2010;Magee et al, 2010;Teckchandani et al, 2010;Kearney et al, 2012;Gabignon et al, 2013), and more recently, rosuvastatin (Cowan et al, 2013). The package insert for sodium fusidate (Fusidin tablets) was also recently amended with additional warnings to reflect the adverse musculoskeletal findings (https://www.medicines.org.uk/emc/medicine/2448).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Eng

Scialis

Rotter

et al. 2016

Drug Metabolism and Disposition

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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 (IC 50 = 295 6 1.0 mM) and time-dependent (K I = 216 6 41 mM and k inact = 0.0179 6 0.001 min 21) inhibitor of CYP3A4-catalyzed midazolam-19-hydroxylase activity in human liver microsomes. FA demonstrated inhibition of multidrug resistant protein 1-mediated digoxin transport with an IC 50 value of 157 6 1.0 mM and was devoid of breast cancer resistance protein inhibition (IC 50 > 500 mM). In contrast, FA showed potent inhibition of OATP1B1-and OATP1B3-specific rosuvastatin transport with IC 50 values of 1.59 mM and 2.47 mM, 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 (IC 50 = 2.26 mM) and Oatp1b2 (IC 50 = 4.38 mM) 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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Eng

Scialis

Rotter

et al. 2016

Drug Metabolism and Disposition

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“…The patients' characteristics are similar to those of 18 previously reported cases (table 2⇓). [6][7][8][9][10][11][12][13][14][15][16][17] .…”

Section: Cohortmentioning

confidence: 99%

Rhabdomyolysis after co-prescription of statin and fusidic acid

Kearney¹,

Carr²,

McConville³

et al. 2012

BMJ

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“…Approximately 30 cases of DDIs between FA and statins have been reported in the literature (3,(6)(7)(8)(9)(10)(11). Because the majority of the reports involved atorvastatin and simvastatin, which are known to be cleared primarily by cytochrome P450 3A4 (CYP3A4), and since there is some evidence of involvement of CYP3A4 in FA disposition, it was assumed that FA reduces the clearance of statins via inhibition of CYP3A4 (9-11).…”

mentioning

confidence: 99%

“…Because the majority of the reports involved atorvastatin and simvastatin, which are known to be cleared primarily by cytochrome P450 3A4 (CYP3A4), and since there is some evidence of involvement of CYP3A4 in FA disposition, it was assumed that FA reduces the clearance of statins via inhibition of CYP3A4 (9)(10)(11). Accordingly, it was suggested that statins which are primarily eliminated by CYP3A4 (atorvastatin and simvastatin) are more likely to result in DDIs when coadministered with FA than statins with minimal elimination by CYP3A4 (rosuvastatin, pravastatin, and fluvastatin) (10). However, there have been two reports with rosuvastatin (3,7), and alternative mechanisms for the DDIs have been proposed (12)(13)(14).…”

mentioning

confidence: 99%

Fusidic Acid Inhibits Hepatic Transporters and Metabolic Enzymes: Potential Cause of Clinical Drug-Drug Interaction Observed with Statin Coadministration

Gupta

Harris

Lin

et al. 2016

Antimicrob Agents Chemother

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bFusidic 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 drugdrug 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 [IC 50 ], ϳ50 to 110 M) and OATP1B1-mediated uptake (IC 50 , ϳ4 to 35 M) 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 ϳ4 mM, and the maximum total or unbound concentration in the inlet to the liver was reported to be up to 223 M or 11 M, respectively, upon multiple dosing). Similarly, FA inhibited metabolism of statins in human liver microsomes (IC 50 , ϳ17 to 195 M). 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.T he evolution of drug-resistant bacteria along with shrinking investments in antimicrobial drug research from pharmaceutical companies has renewed interest in older antibiotics. The Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA) has emphasized the urgency to address this public health concern and highlighted methicillinresistant Staphylococcus aureus (MRSA) as one of the major resistant pathogens without enough treatment options (1). Fusidic acid (FA) has been used to treat MRSA in many countries for several decades due to continued low resistance rates (2).Cases of drug-drug interactions (DDIs) have been reported upon FA coadministration with drugs of various classes, such as HIV protease inhibitors (ritonavir and saquinavir), immunosuppressants (cyclosporine [CsA]), oral anticoagulants (such as coumarin derivatives), and statins (atorvastatin and simvastatin) (3-5). While the actual number of cases reported is small, the usage of FA is expected to increase given its continued effectiveness against resistant bacterial strains, with potential for a concomitant rise in DDIs.Approximately 30 cases of DDIs between FA and statins have been reported in the literature (3,(6)(7)(8)(9)(10)(11). Because the majority of the reports involved atorvastatin ...

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Rhabdomyolysis following co-prescription of fusidic acid and atorvastatin

Abstract: Campbell for her help with this manuscript. 2010; 40:33-6 Rhabdomyolysis following co-prescription of fusidic acid and atorvastatin J R Coll Physicians Edinb

Cited by 18 publications

References 22 publications

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

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

Rhabdomyolysis after co-prescription of statin and fusidic acid

Fusidic Acid Inhibits Hepatic Transporters and Metabolic Enzymes: Potential Cause of Clinical Drug-Drug Interaction Observed with Statin Coadministration

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