Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metabolism and disposition of capravirine, a new non-nucleoside reverse transcriptase inhibitor, were studied in healthy male volunteers who were randomly divided into two groups (A and B) with five subjects in each group. Group A received a single oral dose of [(14)C]capravirine (1400 mg) and group B received multiple oral doses of ritonavir (100 mg), followed by a single oral dose of [(14)C]capravirine (1400 mg). Mean total recoveries of radioactivity for groups A and B were 86.3% and 79.0%, respectively, with a mean cumulative recovery in urine comparable with that in feces for both groups. Excretion of unchanged capravirine was negligible in urine and low in feces for both groups. The results suggest that capravirine was well absorbed, with metabolism as the principal mechanism of clearance. Capravirine underwent extensive metabolism to a variety of metabolites via oxygenations (mono-, di-, tri-, and tetra-) representing the predominant pathway, glucuronidation, and sulfation in humans. No useful plasma profiles of group A were obtained due to extremely low levels of plasma radioactivity. Analysis of group B plasma indicated that unchanged capravirine was the major radiochemical component, with three monooxygenated products and a glucuronide of capravirine as the major circulating metabolites. Nineteen metabolites were identified using liquid chromatography-multistage ion-trap mass spectrometry methodologies. In summary, coadministration of low-dose ritonavir (a potent CYP3A4 inhibitor) drastically decreased the levels of sequential oxygenated metabolites and markedly increased the levels of the parent drug and primary oxygenated metabolites overall in plasma, urine, and feces.
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PMID:Metabolism and excretion of capravirine, a new non-nucleoside reverse transcriptase inhibitor, alone and in combination with ritonavir in healthy volunteers. 1520 83

Capravirine, a non-nucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1, undergoes extensive oxygenations to numerous sequential metabolites in humans. Because several possible oxygenation pathways may be involved in the formation and/or sequential metabolism of a single metabolite, it is very difficult or even impossible to determine the definitive pathways and their relative contributions to the overall metabolism of capravirine using conventional approaches. For this reason, a human liver microsome-based "sequential incubation" method has been developed to deconvolute the complicated sequential metabolism of capravirine. In brief, the method includes three fundamental steps: 1) 30-min primary incubation of [(14)C]capravirine, 2) isolation of (14)C metabolites from the primary incubate, and 3) 30-min sequential incubation of each isolated (14)C metabolite supplemented with an ongoing (30 min) microsomal incubation with nonlabeled capravirine. Based on the extent of both the disappearance of the isolated precursor (14)C metabolites and the formation of sequential (14)C metabolites, definitive oxygenation pathways of capravirine were assigned. In addition, the percentage contribution of a precursor metabolite to the formation of each of its sequential metabolites (called sequential contribution) and the percentage contribution of a sequential metabolite formed from each of its precursor metabolites (called precursor contribution) were determined. An advantage of this system is that the sequential metabolism of each isolated (14)C metabolite can be monitored selectively by radioactivity in the presence of all relevant metabolic components (i.e., nonlabeled parent and its other metabolites). This methodology should be applicable to mechanistic studies of other compounds involving complicated sequential metabolic reactions when radiolabeled materials are available.
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PMID:A simple sequential incubation method for deconvoluting the complicated sequential metabolism of capravirine in humans. 1600 66

Capravirine (CPV; formerly AG1549 and S-1153) is a novel, nonnucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1) that has demonstrated potent in vitro antiviral activity against several HIV-1 laboratory strains and clinical isolates with EC50 values ranging from 0.7 to 10.3 nM. In this study, we evaluated the resistance and cross-resistance profiles of CPV through selection of resistant HIV-1 variants from in vitro serial passage of HIV-1 NL4-3 and HIV-1 IIIB and by performing susceptibility assays on HIV-1 variants constructed to contain CPV-specific amino acid substitutions in reverse transcriptase (RT). Results demonstrate that HIV-1 variants selected at increasing CPV concentrations contained multiple substitutions in diverse patterns including L100I, Y181C, G190E and/or L234I in various combinations with K101R/E, K103T, V106A/I, V108I, E138K, T139K, A158T, V179D/I/G, Y188D, V189I, G190A, F227C, W229R, L234F, M230I/L and P236H/T. Interestingly, HIV-1 variants constructed to contain the T215Y zidovudine (AZT)-resistance associated substitution with CPV-resistance associated substitutions V106A, Y181C, F227C, F227L, L234I or V106A/F227L demonstrated 2.4-5.4-fold increased susceptibility to CPV. Results also demonstrate that the CPV-resistance associated substitutions Y181C, F227C, F227L and L234I reverse the phenotypic resistance to AZT conferred by the T215Y substitution.
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PMID:In vitro selection of mutations in human immunodeficiency virus type 1 reverse transcriptase that confer resistance to capravirine, a novel nonnucleoside reverse transcriptase inhibitor. 1647 77

Capravirine, a new non-nucleoside reverse transcriptase inhibitor, undergoes extensive oxygenation reactions, including N-oxidation, sulfoxidation, sulfonation, and hydroxylation in humans. Numerous primary (mono-oxygenated) and sequential (di-, tri-, and tetraoxygenated) metabolites of capravirine are formed via the individual or combined oxygenation pathways. In this study, cytochrome P450 enzymes responsible for the primary and sequential oxygenation reactions of capravirine in human liver microsomes were identified at the specific pathway level. The total oxygenation of capravirine is mediated predominantly (>90%) by CYP3A4 and marginally (<10%) by CYP2C8, 2C9, and 2C19 in humans. Specifically, each of the two major mono-oxygenated metabolites C23 (sulfoxide) and C26 (N-oxide), is mediated predominantly (>90%) by CYP3A4 and slightly (<10%) by CYP2C8, the minor tertiary hydroxylated metabolite C19 by CYP3A4, 2C8, and 2C19, and the minor primary hydroxylated metabolite C20 by CYP3A4, 2C8, and 2C9. However, all sequential oxygenation reactions are mediated exclusively by CYP3A4. Due to their relatively insignificant contributions of C19 and C20 to total capravirine metabolism, no attempt was made to determine relative contributions of cytochrome P450 enzymes to the formation of the two minor metabolites.
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PMID:Identification of enzymes responsible for primary and sequential oxygenation reactions of capravirine in human liver microsomes. 1691 10