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.
Footnotes
- Received September 17, 2013.
- Accepted November 8, 2013.
This work was supported by the National Institutes of Health National Center for Research Resources [Grant COBRE 5P20-RR021940]; the National Institute of General Medical Sciences [Grant 8P20-GM103549-7]; and the National Institute of Allergy and Infectious Diseases [Grant AI095425].
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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