On the Metabolism of Fusidic Acid in Man.

Godtfredsen, W. O.; Vangedal, S.; Kaufmann, Frantz; Motzfeldt, K.; Williams, Dudley H.; Bunnenberg, E.; Djerassi, Carl; Records, Ruth

doi:10.3891/acta.chem.scand.20-1599

Cited by 42 publications

(19 citation statements)

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“…Indeed, the major elimination pathway of fusidic acid is hepatic metabolism; this is followed by exclusive biliary elimination of these metabolites. Of the numerous biotransformation products eliminated in bile, the major ones are the glucuroconjugate of fusidic acid, the dicarboxylic metabolite, and a hydroxy derivative of the dicarboxylic metabolite (9). Only very small amounts of fusidic acid and 3-ketofusidic acid are found in bile.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…Its antibacterial activity is the result of an inhibition of bacterial protein synthesis (1). This drug, which is 95 to 97% bound to plasma albumin (11), is exclusively cleared by hepatic metabolism (9). Fusidic acid is poorly soluble in water (8); therefore, two intravenous formulations have been developed: the diethanolamine salt and the sodium salt.…”

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confidence: 99%

Pharmacokinetics of intravenous fusidic acid in patients with cholestasis

Peter

Jehl

Pottecher

et al. 1993

Antimicrob Agents Chemother

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“…In addition, it has a long plasma halflife of 10 -14 h and is highly (.95%) but reversibly protein bound (Reeves 1987;Turnidge 1999). Attempts have been made to obtain fusidic acid analogs with improved pharmacokinetic/pharmocodynamic properties and a large number of semisynthetic analogs have been synthesized (Godtfredsen and Vangedal 1966). Some modifications were made that retain activity including saturation of the C24 -C25 double bond, replacement of the 16a-acetoxyl group by other groups, and conversion of the 11-hydroxyl group into the corresponding ketone.…”

Section: Spectrum Of Activitymentioning

confidence: 99%

Fusidic Acid: A Bacterial Elongation Factor Inhibitor for the Oral Treatment of Acute and Chronic Staphylococcal Infections

Fernandes

2016

Cold Spring Harb Perspect Med

107

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Fusidic acid is an oral antistaphylococcal antibiotic that has been used in Europe for more than 40 years to treat skin infections as well as chronic bone and joint infections. It is a steroidal antibiotic and the only marketed member of the fusidane class. Fusidic acid inhibits protein synthesis by binding EF-G-GDP, which results in the inhibition of both peptide translocation and ribosome disassembly. It has a novel structure and novel mode of action and, therefore, there is little cross-resistance with other known antibiotics. Many mutations can occur in the FusA gene that codes for EF-G, and some of these mutations can result in high-level resistance (minimum inhibitory concentration [MIC] . 64 mg/L), whereas others result in biologically unfit staphylococci that require compensatory mutations to survive. Low-level resistance (,8 mg/L) is more common and is mediated by fusB, fusC, and fusD genes that code for small proteins that protect EF-G-GDP from binding fusidic acid. The genes for these proteins are spread by plasmids and can be selected mostly by topical antibiotic use. Reports of resistance have led to combination use of fusidic acid with rifampin, which is superseded by the development of a new dosing regimen for fusidic acid that can be used in monotherapy. It consists of a front-loading dose to decrease the potential for resistance development followed by a maintenance dose. This dosing regimen is now being used in clinical trials in the United States for skin and refractory bone and joint infections.

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“…While at least three of the seven identified fusidic acid metabolites have antimicrobial activity (7,8), such activity is less than that of fusidic acid. Given that fusidic acid has never been evaluated according to the requirements of modern drug development, major clinically relevant gaps exist in our understanding of its pharmacokinetics (PK).…”

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confidence: 99%

Population Pharmacokinetics of Fusidic Acid: Rationale for Front-Loaded Dosing Regimens Due to Autoinhibition of Clearance

Bulitta

Okusanya

Forrest

et al. 2013

Antimicrob Agents Chemother

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The objectives of this analysis were to develop a population pharmacokinetic (PK) model to describe the absorption and disposition of fusidic acid after single and multiple doses and to determine the effect of food on the rate and extent of bioavailability. Plasma PK data from three phase 1 studies (n ‫؍‬ 75; n ‫؍‬ 14 with and without food) in which healthy subjects received sodium fusidate (500 to 2,200 mg) as single or multiple oral doses every 8 h (q8h) or q12h for up to 7 days were modeled using S-ADAPT (MCPEM algorithm). Accumulation of fusidic acid after multiple doses was more than that predicted based on single-dose data. The PK of fusidic acid was best described using a time-dependent mixed-order absorption process, two disposition compartments, and a turnover process to describe the autoinhibition of clearance. The mean total clearance (% coefficient of variation) was 1.28 liters/h (33%) and the maximum extent of autoinhibition was 71.0%, with a 50% inhibitory concentration (IC 50 ) of 46.3 mg/liter (36%). Food decreased the extent of bioavailability by 18%. As a result of the autoinhibition of clearance, steady state can be achieved earlier with dosing regimens that contain higher doses (after 8 days for 750 mg q12h and 1 day for 1,500 mg q12h on day 1 followed by 600 mg q12h versus 3 weeks for 500 mg q12h). Given that large initial doses autoinhibit the clearance of fusidic acid, this characteristic provides a basis for the administration of front-loaded dosing regimens of sodium fusidate which would allow for effective concentrations to be achieved early in therapy.

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On the Metabolism of Fusidic Acid in Man.

Cited by 42 publications

References 0 publications

Pharmacokinetics of intravenous fusidic acid in patients with cholestasis

Pharmacokinetics of intravenous fusidic acid in patients with cholestasis

Fusidic Acid: A Bacterial Elongation Factor Inhibitor for the Oral Treatment of Acute and Chronic Staphylococcal Infections

Population Pharmacokinetics of Fusidic Acid: Rationale for Front-Loaded Dosing Regimens Due to Autoinhibition of Clearance

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