RT Journal Article SR Electronic T1 CPY3A4-Mediated α-Hydroxyaldehyde Formation in Saquinavir Metabolism JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 213 OP 220 DO 10.1124/dmd.113.054874 VO 42 IS 2 A1 Feng Li A1 Jie Lu A1 Xiaochao Ma YR 2014 UL http://dmd.aspetjournals.org/content/42/2/213.abstract AB 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.