title: CPY3A4-mediated α-hydroxyaldehyde formation in saquinavir metabolism.
abstract: Saquinavir (SQV) is a protease inhibitor widely used for the treatment of human immunodeficiency virus (HIV) infection. We profiled SQV metabolism in mice using a metabolomic approach. Thirty SQV metabolites were identified in mouse feces and urine, of which 20 are novel. Most metabolites observed in mice were recapitulated in human liver microsomes. Among these novel metabolites, one α-hydroxyaldehyde produced from SQV N-dealkylation was noted and verified for the first time. Meanwhile, the corresponding product (3S)-N-tert-butyldecahydro-isoquinoline-3-carboxamide and its further metabolites were identified in mouse urine. The α-hydroxyaldehyde pathway was confirmed by using semicarbazide as a trapping reagent as well. Using recombinant cytochrome P450 (CYP450) isoenzymes and Cyp3a-null mice, CYP3A was identified as the dominant enzyme contributing to the formation of α-hydroxyaldehyde. This study enhances our knowledge of SQV metabolism, which can be used for predicting drug-drug interactions and further understanding the mechanism of adverse effects associated with SQV.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (F.L.); Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania (J.L., X.M.).
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Ma
mesh_terms: D000447:Aldehydes / Q000378:metabolism* / Q000652:urine; D000818:Animals; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003640:Dealkylation; D005243:Feces / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000378:metabolism* / Q000652:urine; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000378:metabolism; D019258:Saquinavir / Q000378:metabolism* / Q000652:urine; D008565:Membrane Proteins
chemical_list: D000447:Aldehydes; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D017320:HIV Protease Inhibitors; D011994:Recombinant Proteins; D019258:Saquinavir; C510163:CYP3A4 protein, human; C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins