Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.16 (HIV-1 protease)
 2,107 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HIV-1 protease inhibitor ritonavir (ABT-538) undergoes cytochrome P450-mediated biotransformation in human liver microsomes to three major metabolites, Ml, M2 and M11, with wide interindividual variation in the rates of metabolite formation. The structures of these metabolites were determined with the use of electrospray ionization mass spectrometry. Chemical inhibition, metabolic correlation, immunoinhibition and metabolism by microsomes derived from specific CYP cDNA-transfected B-lymphoblastoid cell lines indicated that the CYP3A subfamily of enzymes was the major contributor to the formation of M1 and M11, whereas both CYP3A and CYP2D6 contributed to the formation of M2. None of the typical CYP3A substrates/inhibitors (e.g., ketoconazole, troleandomycin) were able to completely inhibit ritonavir metabolism, even at high concentrations. Ritonavir was found to be a potent inhibitor of CYP3A-mediated biotransformations (nifedipine oxidation, IC50) = 0.07 microM; 17alpha-ethynylestradiol 2-hydroxylation, IC50 = 2 microM; terfenadine hydroxylation, IC50 = 0.14 microM). Ritonavir was also found to be an inhibitor of the reactions mediated by CYP2D6 (IC50 = 2.5 microM) and CYP2C9/10 (IC50 = 8.0 microM). The results of this study indicate the potential for in vivo inhibition of the metabolism by ritonavir of drugs that are CYP3A, CYP2D6 and, to a lesser extent, CYP2C9/10 substrates.
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PMID:Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. 861 51

PNU-106893, N-{3-[1-(4-hydroxy-2-oxo-6-phenyl-6-propyl-5, 6-dihydro-2H-pyran-3-yl)-2, 2-dimethylpropyl]phenyl}-1-methyl-1H-imidazole-4-sulfonamide, is a selective HIV aspartyl protease inhibitor under evaluation as a potential oral treatment of acquired immunodeficiency disease. PNU-106893 is a mixture of four stereoisomers, designated PNU-109165 (3alphaR, 6S), PNU-109166 (3alphaR, 6R), PNU-109167 (3alphaS, 6S), and PNU-109168 (3alphaS, 6R). The major P450 isoforms involved in the metabolism of PNU-106893 and its pure stereoisomers are identified as CYP2D6 and CYP3A4. The major oxidative biotransformation pathway of PNU-106893 which occurs in microsomal incubations appears to be hydroxylation of the phenylethyl side chain attached to the C-6 carbon of the dihydropyrone ring. This hydroxylation is mediated by CYP2D6 only and the process is stereoselective for the 6R absolute stereochemistry. The configuration at position 3 appears to play a minor role in the CYP2D6 mediated hydroxylation. These insights have impacted drug candidate selection for this class of compounds.
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PMID:Stereoselective hydroxylation of nonpeptidic HIV protease inhibitors by CYP2D6. 1050 34