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Journal of Pharmacology and Experimental Therapeutics

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Abstract

Time- and dose-dependent pharmacokinetics of L-754,394, an HIV protease inhibitor, in rats, dogs and monkeys.

J H Lin, M Chiba, I W Chen, K J Vastag, J A Nishime, B D Dorsey, S R Michelson and S L McDaniel
Journal of Pharmacology and Experimental Therapeutics July 1995, 274 (1) 264-269;
J H Lin
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M Chiba
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I W Chen
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K J Vastag
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J A Nishime
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B D Dorsey
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S R Michelson
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S L McDaniel
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Abstract

L-754,394 is a potent and specific inhibitor of the HIV-1 encoded protease that is essential for the maturation of the infectious virus. The drug exhibited dose-dependent kinetics in all species studied (rat, dog and monkey); the apparent clearance decreased when the dose was increased. However, the dose-dependency cannot be explained by Michaelis-Menten kinetics. L-754,394 in plasma declined log-linearly with time, but with an apparent half-life that increased with dose. The apparent terminal half-life of L-754,394 in rats increased from 20 min at 0.5 mg/kg i.v. to 118 min at 10 mg/kg i.v. Furthermore, L-754,394 exhibited time-dependent pharmacokinetics. After chronic i.v. doses for 7 days (1 mg/kg/dose/day), the apparent clearance of L-754,394 in rats decreased from 87 ml/min/kg after the first dose to 25 ml/min/kg after the last dose. Similar results were observed in dogs and monkeys. In vitro spectral studies indicated that approximately 40 to 60% of the content of cytochrome P-450 was inactivated when L-754,394 (10 microM) was incubated with rat, dog and monkey liver microsomes in the presence of NADPH. Little or no inactivation of cytochrome P-450 was observed when either NADPH or L-754,394 was omitted. In addition, L-754,394 selectively inhibited CYP 2C11-dependent testosterone 2 alpha- and 16 alpha-hydroxylase activity and CYP 3A1/2-dependent testosterone 6 beta-hydroxylase activity, but not CYP 2D1/2-dependent bufuralol 1'-hydroxylase activity nor CYP 1A2-dependent phenacetin O-deethylase activity in rat liver microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

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Journal of Pharmacology and Experimental Therapeutics
Vol. 274, Issue 1
1 Jul 1995
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Abstract

Time- and dose-dependent pharmacokinetics of L-754,394, an HIV protease inhibitor, in rats, dogs and monkeys.

J H Lin, M Chiba, I W Chen, K J Vastag, J A Nishime, B D Dorsey, S R Michelson and S L McDaniel
Journal of Pharmacology and Experimental Therapeutics July 1, 1995, 274 (1) 264-269;

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Abstract

Time- and dose-dependent pharmacokinetics of L-754,394, an HIV protease inhibitor, in rats, dogs and monkeys.

J H Lin, M Chiba, I W Chen, K J Vastag, J A Nishime, B D Dorsey, S R Michelson and S L McDaniel
Journal of Pharmacology and Experimental Therapeutics July 1, 1995, 274 (1) 264-269;
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