The disposition and pharmacokinetics of ketoconazole in the rat

R. P. Remmel, K. Amoh, M. M. Abdel-Monem

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23 Scopus citations

Abstract

The disposition, biliary excretion, and pharmacokinetics of ketoconazole in Sprague-Dawley rats were determined after intravenous administration. Greater than 80% of the radioactivity after a 5 mg/kg iv dose of 3H-ketoconazole was excreted in the feces. Urinary excretion was essentially complete after 48 hr; however, fecal excretion was prolonged over a 7-day period. Biliary excretion of radioactivity averaged 54.3 ± 18.0% of the dose over a 7.5-8-hr period in pentobarbital-anesthesized rats. The possibility of enterohepatic recirculation was examined using a linked rat technique. Less than 2% of the radioactivity was found in the recipient bile over 9-12 hr. In eight male rats, the plasma pharmacokinetics of ketoconazole, as determined by an HPLC assay with fluorescence detection, were as follows: V(D) = 655 ± 91 ml/kg, Cl = 14.4 ± 5.1 ml/min/kg, and t 1/2 = 35.0 ± 12.3 min. Three of the rats were given an additional oral dose to determine absolute bioavailability. The time to peak was 30-60 min, and the bioavailability was 35.8 ± 3.55%. Previous studies have indicated that ketoconazole is well absorbed in rats; therefore, the poor bioavailability is probably due to first pass metabolism. The prolonged fecal excretion of radioactivity from an intravenous dose was probably caused by slow elimination of ketoconazole metabolites.

Original languageEnglish (US)
Pages (from-to)735-739
Number of pages5
JournalDrug Metabolism and Disposition
Volume15
Issue number6
StatePublished - 1987

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