Abstract
Tipranavir (TPV) is the first nonpeptidic protease inhibitor used for the treatment of drug-resistant HIV infection. Clinically, TPV is coadministered with ritonavir (RTV) to boost blood concentrations and increase therapeutic efficacy. The mechanism of metabolism-mediated drug interactions associated with RTV-boosted TPV is not fully understood. In the current study, TPV metabolism was investigated in mice using a metabolomic approach. TPV and its metabolites were found in the feces of mice but not in the urine. Principal component analysis of the feces metabolome uncovered eight TPV metabolites, including three monohydroxylated, three desaturated, one dealkylated, and one dihydroxylated. In vitro study using human liver microsomes recapitulated five TPV metabolites, all of which were suppressed by RTV. CYP3A4 was identified as the primary enzyme contributing to the formation of four TPV metabolites (metabolites II, IV, V, and VI), including an unusual dealkylated product arising from carbon-carbon bond cleavage. Multiple cytochromes P450 (2C19, 2D6, and 3A4) contributed to the formation of a monohydroxylated metabolite (metabolite III). In vivo, RTV cotreatment significantly inhibited eight TPV metabolic pathways. In summary, metabolomic analysis revealed two known and six novel TPV metabolites in mice, all of which were suppressed by RTV. The current study provides solid evidence that the RTV-mediated boosting of TPV is due to the modulation of P450-dependent metabolism.
Footnotes
This work was supported by the National Institutes of Health National Center for Research Resources [Grant COBRE 5P20-RR021940].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.030817.
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- TPV
- tipranavir
- PI
- protease inhibitor
- RTV
- ritonavir
- P450
- cytochrome P450
- TPV/r
- tipranavir and ritonavir
- HLM
- human liver microsomes
- UPLC
- ultraperformance liquid chromatography
- TOFMS
- time-of-flight mass spectrometry
- MLM
- mouse liver microsomes
- PBS
- phosphate-buffered saline
- rcf
- relative centrifugal force
- PCA
- principal components analysis
- OPLS-DA
- orthogonal projection to latent structures-discriminant analysis
- MS/MS
- tandem mass spectrometry.
- Received October 14, 2009.
- Accepted January 26, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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