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Vol. 302, Issue 3, 1228-1237, September 2002

In Vitro, Pharmacokinetic, and Pharmacodynamic Interactions of Ketoconazole and Midazolam in the Rat

Tsutomu Kotegawa, Bart E. Laurijssens1, Lisa L. von Moltke, Monette M. Cotreau, Michael D. Perloff, Karthik Venkatakrishnan, Jill S. Warrington, Brian W. Granda, Jerold S. Harmatz and David J. Greenblatt

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, and Division of Clinical Pharmacology, Tufts-New England Medical Center, Boston, Massachusetts

Interactions of midazolam and ketoconazole were studied in vivo and in vitro in rats. Ketoconazole (total dose of 15 mg/kg intraperitoneally) reduced clearance of intravenous midazolam (5 mg/kg) from 79 to 55 ml/min/kg (p < 0.05) and clearance of intragastric midazolam (15 mg/kg) from 1051 to 237 ml/min/kg (p < 0.05), increasing absolute bioavailability from 0.11 to 0.36 (p < 0.05). Presystemic extraction occurred mainly across the liver as opposed to the gastrointestinal tract mucosa. Midazolam increased electroencephalographic (EEG) amplitude in the beta -frequency range. Ketoconazole shifted the concentration-EEG effect relationship rightward (increase in EC50), probably because ketoconazole is a neutral benzodiazepine receptor ligand. Ketoconazole competitively inhibited midazolam hydroxylation by rat liver and intestinal microsomes in vitro, with nanomolar Ki values. At a total serum ketoconazole of 2 µg/ml (3.76 µM) in vivo, the predicted reduction in clearance of intragastric midazolam by ketoconazole (to 6% of control) was slightly greater than the observed reduction in vivo (to 15% of control). However, unbound serum ketoconazole greatly underpredicted the observed clearance reduction. Although the in vitro and in vivo characteristics of midazolam in rats incompletely parallel those in humans, the experimental model can be used to assess aspects of drug interactions having potential clinical importance.

1 Current address: GlaxoSmithKline Research and Development Ltd., Greenford, UK

0022-3565/02/3023-1228$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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