PT - JOURNAL ARTICLE AU - Feng Li AU - Laiyou Wang AU - Grace L Guo AU - Xiaochao Ma TI - Metabolism mediated drug interactions associated with ritonavir-boosted tipranavir in mice AID - 10.1124/dmd.109.030817 DP - 2010 Jan 26 TA - Drug Metabolism and Disposition PG - dmd.109.030817 4099 - http://dmd.aspetjournals.org/content/early/2010/01/26/dmd.109.030817.short 4100 - http://dmd.aspetjournals.org/content/early/2010/01/26/dmd.109.030817.full AB - Tipranavir (TPV) is the first non-peptidic protease inhibitor used for the treatment of drug-resistant HIV infection. Clinically, TPV is co-administered 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 metabolites. 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 co-treatment significantly inhibited eight TPV metabolic pathways. In summary, metabolomic analysis revealed two known and six novel TPV metabolites in mice, and 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.The American Society for Pharmacology and Experimental Therapeutics