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CPY3A4-mediated α-hydroxyaldehyde formation in saquinavir metabolism
1Department 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.).
Drug Metabolism and Disposition: the Biological Fate of Chemicals
|November 12, 2013
Summary
This study identified 30 saquinavir (SQV) metabolites in mice, including 20 novel ones. Cytochrome P450 3A (CYP3A) is the primary enzyme responsible for a key α-hydroxyaldehyde metabolite formation.
Area of Science:
- Pharmacology
- Metabolomics
- Drug Metabolism
Background:
- Saquinavir (SQV) is a crucial protease inhibitor for treating human immunodeficiency virus (HIV) infection.
- Understanding SQV metabolism is vital for optimizing treatment and predicting adverse drug reactions.
Purpose of the Study:
- To comprehensively profile Saquinavir (SQV) metabolites in mice using a metabolomic approach.
- To identify novel metabolites and elucidate the metabolic pathways and enzymes involved in SQV biotransformation.
Main Methods:
- Metabolomic analysis of SQV metabolites in mouse feces and urine.
- In vitro studies using human liver microsomes and recombinant cytochrome P450 (CYP450) isoenzymes.
- In vivo studies utilizing Cyp3a-null mice and semicarbazide as a trapping reagent.
Main Results:
- Thirty SQV metabolites were identified in mice, with 20 being novel.
- A novel α-hydroxyaldehyde metabolite, formed via N-dealkylation, was identified and verified.
- Cytochrome P450 3A (CYP3A) was confirmed as the dominant enzyme in α-hydroxyaldehyde formation.
Conclusions:
- This research significantly expands the known metabolic profile of Saquinavir (SQV).
- The identification of novel metabolites and pathways provides crucial insights into SQV biotransformation.
- Findings support better prediction of drug-drug interactions and understanding of SQV-associated adverse effects.
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