Fusidic acid-induced hyperbilirubinemia

Kutty, Karunakaran P.; Nath, Iyunni V. S.; Kothandaraman, Kalyanapuram R.; Barrowman, J. A.; Perkins, Philip G.; Mu-Ung, P.; Huang, Shao-Nan

doi:10.1007/bf01296717

Cited by 15 publications

(7 citation statements)

References 26 publications

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“…Finally, our findings also raise an intriguing possibility that the clinical cases of hyperbilirubinemia/jaundice noted with FA use (Humble et al, 1980;Kutty et al, 1987;Haddad et al, 1993) could be potentially linked to its inhibitory effects on the OATP1B1-and OATP1B3-mediated bilirubin transport into the liver. Hepatic uptake of bilirubin by OATPs constitutes the first step in the multifaceted elimination process of the heme breakdown product (Cui et al, 2001); a combination of inhibitory effects on bilirubin uptake and/or bilirubin glucuronidation in the liver has emerged as a common theme among drugs associated with clinical hyperbilirubinemia (Chiou et al, 2014).…”

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confidence: 97%

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: Downloaded Frommentioning

confidence: 97%

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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“…Fusidic acid is excreted in the bile and has been associated with both cholestatic injury and hyperbilirubinemia occurring as an isolated finding. 68,69 ANTITUBERCULOSIS CHEMOTHERAPY Drugs used against tuberculosis frequently lead to hepatotoxicity. Significant liver enzyme elevations occur in up to 20% of those treated, especially among elderly people.…”

Section: Fusidic Acidmentioning

confidence: 99%

Hepatotoxicity of Antimicrobial Agents

Brown

Desmond²

2002

Semin Liver Dis

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Antimicrobial agents are a common and important cause of hepatotoxicity. As a class, the antimicrobials contain many and varied structures, leading to a wide clinical spectrum of hepatotoxicity. Minor liver injury, manifest only as liver enzyme elevations, is common with some antimicrobials. Clinically significant injury is unusual but can adopt almost any form. Classical acute hepatocellular, cholestatic, or mixed reactions are most often seen. Other forms of hepatotoxicity including granulomatous reactions, steatosis, chronic hepatitis, and cirrhosis have also been described. Generally, antimicrobial-associated hepatotoxicity is mild and self-limited; most cases resolve after withdrawal of the offending medication. Occasionally, however, liver injury presents as a fulminant life-threatening condition or may develop into a chronic illness with significant morbidity. This article presents a summary of reported hepatotoxicity associated with the major classes of antimicrobials and, where possible, identifies potential risk factors and management strategies to assist clinical practice.

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“…This side effect occurs particularly if excessive doses are administered and if the drug is infused too rapidly (1). The mechanism of fusidic acid-associated jaundice may be due to intrahepatic cholestasis because of competition with the excretory pathways of hepatic bile acids related to the steroid-like structure of the drug (12,13 jaundice is reversible either during therapy or shortly after its interruption (12,16).…”

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Pharmacokinetics of intravenous fusidic acid in patients with cholestasis

Peter

Jehl

Pottecher

et al. 1993

Antimicrob Agents Chemother

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The pharmacokinetics of fusidic acid and 3-ketofusidic acid were investigated in cholestatic and noncholestatic patients after intravenous administration of single and multiple doses of 500 mg of sodium fusidate. The patients, all with low serum albumin levels, were divided into three groups. Group I consisted of six noncholestatic patients; group II consisted of nine mildly cholestatic patients with mild hepatic impairment (conjugated bilirubin, 47 pmol liter-l; alkaline phosphatase, 280 IU liter-'; y-tglutamyltranspeptidase, 190 IU liter-.); group m consisted of six benign intrahepatic cholestatic patients with high isolated conjugated hyperbilirubinemia (98.1 ,umol liter-'). Assays were performed by high-pressure liquid chromatography. At steady state, the mean peak concentrations in serum were 63.7, 44.9, and 92.2 tLg ml-l in groups I, II, and III, respectively; over a dosage interval, areas under the concentration-time curve were 411. 1, 238.7, and 603.4 t.g. h ml-' and the mean body clearances were 0.34, 0.53, and 0.25 ml min kg-' in groups I, II, and III, respectively. The accumulation ratio of fusidic acid increased from 2.8 and 2.4 in groups I and II to 4.2 in group II. At steady state, the ratios of the areas under the concentration-time curve from 0 to 8 h for 3-ketofusidic acid/fusidic acid were 0.11, 0.09, and 0.10 in the three groups, respectively. Only very small amounts of fusidic acid and 3-ketofusidic acid were found in urine. These results substantiate the following hypotheses. In group I and II patients the clearance is higher than that in healthy volunteers because of the increased free, unbound fraction of fusidic acid, a consequence of lower serum albumin concentrations, resulting in increased distribution in tissue and hepatic metabolism. In group MII patients, the higher bilirubinemia results in competition with fusidic acid for the limited glucuronidation mechanism, thus compensating for the increased elimination of fusidic acid because of the low serum albumin concentration. These results suggest that fusidic acid can be administered normally even to patients with high bilirubinemia because the postoperative serum albumin concentration is usually low.

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Fusidic acid-induced hyperbilirubinemia

Cited by 15 publications

References 26 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

Hepatotoxicity of Antimicrobial Agents

Pharmacokinetics of intravenous fusidic acid in patients with cholestasis

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