Metabolism-mediated drug interactions associated with ritonavir-boosted tipranavir in mice.
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.
Li
Feng
F
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Wang
Laiyou
L
Guo
Grace L
GL
Ma
Xiaochao
X
D000825:Animal Structures / Q000378:metabolism; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055162:Biocatalysis / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D003640:Dealkylation; D004347:Drug Interactions; D005243:Feces / Q000737:chemistry; D006801:Humans; D006900:Hydroxylation; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction; D025341:Principal Component Analysis; D011725:Pyridines / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D011753:Pyrones / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D019438:Ritonavir / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013449:Sulfonamides; D014018:Tissue Distribution / Q000187:drug effects
D019380:Anti-HIV Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D011725:Pyridines; D011753:Pyrones; D011994:Recombinant Proteins; D013449:Sulfonamides; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C450259:CYP2C8 protein, human; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019438:Ritonavir; C107201:tipranavir