Metabolism-mediated drug interactions associated with ritonavir-boosted tipranavir in mice.

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.
Authors	Feng Li, Laiyou Wang, Grace L Guo, Xiaochao Ma
Journal	Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 38 Issue 5 Pg. 871-8 (May 2010) ISSN: 1521-009X [Electronic] United States
PMID	20103582 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Anti-HIV Agents Cytochrome P-450 CYP2D6 Inhibitors Cytochrome P-450 CYP3A Inhibitors Pyridines Pyrones Recombinant Proteins Sulfonamides Aryl Hydrocarbon Hydroxylases CYP2C19 protein, human CYP2C8 protein, human Cytochrome P-450 CYP2C19 Cytochrome P-450 CYP2C8 Cytochrome P-450 CYP2D6 Cytochrome P-450 CYP3A CYP3A4 protein, human Ritonavir tipranavir
Topics	Animal Structures (metabolism) Animals Anti-HIV Agents (blood, metabolism, pharmacology) Aryl Hydrocarbon Hydroxylases (antagonists & inhibitors, genetics, metabolism) Biocatalysis (drug effects) Chromatography, High Pressure Liquid Cytochrome P-450 CYP2C19 Cytochrome P-450 CYP2C8 Cytochrome P-450 CYP2D6 (genetics, metabolism) Cytochrome P-450 CYP2D6 Inhibitors Cytochrome P-450 CYP3A (genetics, metabolism) Cytochrome P-450 CYP3A Inhibitors Dealkylation Drug Interactions Feces (chemistry) Humans Hydroxylation Metabolomics (methods) Mice Mice, Inbred Strains Microsomes, Liver (drug effects, metabolism) Molecular Structure Oxidation-Reduction Principal Component Analysis Pyridines (blood, metabolism, pharmacology) Pyrones (blood, metabolism, pharmacology) Recombinant Proteins (metabolism) Ritonavir (pharmacology) Spectrometry, Mass, Electrospray Ionization Sulfonamides Tissue Distribution (drug effects)

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