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In vitro Metabolism of a Potent HIV‐protease Inhibitor (141W94) Using Rat, Monkey and Human Liver S9
Author(s) -
Singh Rominder,
Chang Sai Y.,
Taylor Lester C. E.
Publication year - 1996
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/(sici)1097-0231(19960715)10:9<1019::aid-rcm618>3.0.co;2-j
Subject(s) - chemistry , in vitro , human immunodeficiency virus (hiv) , protease , protease inhibitor (pharmacology) , metabolism , biochemistry , pharmacology , virology , enzyme , viral load , antiretroviral therapy , medicine , biology
Abstract Compound 141W94 (Vertex VX478) (3 S )‐tetrahydro‐3‐furyl N ‐[( S , 2 R )‐3‐(4‐amino‐ N ‐isobutylbenzenesulfonamido)‐1‐benzyl‐2‐hydroxypropyl] carbamate, is a potent HIV‐protease inhibitor and is currently undergoing clinical trials. The purpose of this study was the rapid identification of the phase I and II in vitro metabolite of 141W94 using mass spectrometry. Four different sources of liver S9 fractions were used for studying comparative in vitro metabolism of 141W94. They were obtained from Arochlor‐induced rat, normal (untreated) rat, cynomolgus monkey and human livers. Selected incubations were supplemented with uridine diphosphate glucuronic acid and the reduced form of glutathione. The predominant species seen in the incubation mixture was the parent compound 141W94. Metabolites arising from ring opening to form the diol and carboxylic acid and oxidation of the tetrahydrofurran ring (formation of dihydrofuran) were identified. In addition, of the two monohydroxylated products identified, one resulted from hydroxylation on the aniline ring and the other from hydroxylation at the benzylic position. Two different glucuronides were also observed. Comparing the three species, very little metabolism was seen in the normal (non‐induced) rat. The metabolic profile and extent of metabolism with induced rat, monkey and human S9 was similar. Induced rat S9 incubation showed the formation of two unique metabolites that were not seen in non‐induced rat, monkey and human S9 fractions. They were the monohydroxylated glucuronide and a carbamate cleavage product. The metabolites were identified using mass spectrometry based on their molecular masses and fragmentation patterns.