title: Dose-dependent toxicokinetics of L-689,502, a potent human immunodeficiency virus protease inhibitor, in rats and dogs.
abstract: L-689,502, N-[2(R)-hydroxy-1(S)-indanyl]-5(S)-(1,1-dimethylethoxy- carbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(4-[2-(4- morpholinyl)ethoxy]phenyl)methyl hexanamide, is a potent inhibitor of human immunodeficiency virus-1 protease. The effect of dose on the elimination kinetics of L-689,502 was studied in rats and dogs. After i.v. administration, total plasma clearance of L-689,502 in rats decreased with increasing dose; the clearance decreased from 181 ml/min/kg at 1 mg/kg to 86 ml/min/kg at 20 mg/kg. Similar results were observed in dogs; clearance fell from 29 ml/min/kg at 0.5 mg/kg to 17 ml/min/kg at 10 mg/kg. Bile flow in rats was retarded in a dose-dependent manner after a single i.v. injection of L-689,502. The cholestatic effect was reversible and maximal at 5 mg/kg i.v. Consistent with the cholestatic effect, L-689,502 caused an increase in serum levels of aminotransferase. After i.v. administration of L-689,502 (10 mg/kg), alanine aminotransferase increased from 50 to 370 IU/liter and aspartate aminotransferase from 120 to 700 IU/liter. Moreover, pretreatment of rats with L-689,502 resulted in a significant decrease in the elimination kinetics of antipyrine and diflunisal, as well as of L-689,502 itself. Collectively, these results suggest that the dose-dependent kinetics of L-689,502 in rats and dogs are more likely due to hepatotoxicity caused by the drug than to capacity-limited metabolism.
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania.
authors.forename: J H
authors.initials: JH
authors.lastname: Lin
authors.forename: I W
authors.initials: IW
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: King
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics; D000818:Animals; D001646:Bile / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D009025:Morpholines / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D010455:Peptides / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001798:Blood Proteins; D017320:HIV Protease Inhibitors; D009025:Morpholines; D010455:Peptides; C072111:L 689502; D000082:Acetaminophen