title: Species-dependent enantioselective pharmacokinetics of PNU-103017, a pyrone HIV protease inhibitor.
abstract: PNU-103017, 4-Cyano-N-(3-(cyclopropyl(5,6,7,8,9,10-hexahydro-4-hydroxy- 2-oxo-2H-cycloocta(b) pyran-3-yl)methyl)phenyl)-benzenesulfonamide, is a selective HIV aspartyl protease inhibitor under evaluation as a potential oral treatment of Acquired Immunodeficiency Diseases. PNU-103017 is a racemic mixture of two enantiomers, designated PNU-103264 (R-) and PNU-103265 (S-). Stereoselective pharmacokinetics of the two enantiomers of PNU-103017 were observed in the dog, rat, and human after single and multiple dose administration of the racemate and were apparently species-dependent. Mean enantiomeric ratios of plasma concentrations (R-/S-) at each time point were greater than 1 in the dog, ranging from 1.22 to 3.06, but less than 1 in the rat and in the human, ranging from 0.44 to 0.80 and 0.23 to 0.73, respectively. A trend towards increased or decreased (farther from 1:1, R-/S-) enantiomeric ratio of plasma concentrations with time after each administration was also observed. The enantiomeric ratio remained unchanged after multiple dose administration in the rat, dog, and human although enzyme induction and increased plasma clearance were observed for both enantiomers.
authors.affiliation: Pharmacia & Upjohn, Kalamazoo, MI 49001, USA. wzhong@am.pnu.com
authors.forename: W Z
authors.initials: WZ
authors.lastname: Zhong
authors.forename: M G
authors.initials: MG
authors.lastname: Williams
authors.forename: M T
authors.initials: MT
authors.lastname: Borin
authors.forename: G E
authors.initials: GE
authors.lastname: Padbury
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D011753:Pyrones / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013449:Sulfonamides / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D017320:HIV Protease Inhibitors; D011753:Pyrones; D013449:Sulfonamides; C107418:PNU 103017