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Species‐dependent enantioselective pharmacokinetics of PNU‐103017, a Pyrone HIV protease inhibitor
Author(s) -
Zhong WeiZhu,
Williams Marta G.,
Borin Marie T.,
Padbury Guy E.
Publication year - 1998
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/(sici)1520-636x(1998)10:3<210::aid-chir2>3.0.co;2-d
Subject(s) - chemistry , enantiomer , pharmacokinetics , stereoselectivity , stereochemistry , oral administration , enantioselective synthesis , pharmacology , enzyme , enzyme inhibitor , chromatography , biochemistry , medicine , catalysis
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. Chirality 10:210 – 216, 1998 . © 1998 Wiley‐Liss, Inc.