UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug discovery is the main flag ship of the pharmaceutical industry in order to ensure that innovations constantly occur in the identification and development of novel therapeutic options for the management of diseases. Recently, research trends that take advantage of the safety and efficacy of marketed products by combining such products with other agents to influence certain clinical pharmacology attribute(s) have emerged. The focus of the review is to evaluate ongoing research trends that have considered leveraging on certain clinical pharmacology attributes in the areas of viral infection (HIV and influenza) and oncology. Case studies discussed in this review include: a) the use of probenecid to block the organic anion renal transport of oseltamivir carboxylate (a key active metabolite of oseltamivir phosphate) to reduce the oral dose of oseltamivir phosphate; b) the use of rifampicin to induce the CYP2C19 enzyme and thereby, promote the formation of a potent active metabolite M8 (nelfinavir hydroxyl-t-butylamide) and achieve sustained blood levels to combat HIV infection along with ritonavir; c) the use of CYP3A4 inhibitors such as ketoconazole, cyclosporin A, ritonavir etc to overcome the extensive presystemic metabolism of docetaxel and enhance the oral bioavailability of docetaxel. Along with the case studies, several hurdles for drug development such as dose selection, frequency of dosing, and duration of the clinical studies, picking the right surrogate(s) for efficacy, evaluation of drug-drug interaction potential with other co-substrates have been discussed in line with the current day requirements for a sound clinical and regulatory strategy. In summary, based on the collated information, a pragmatic approach would render feasibility for a balanced therapy management using combined clinical pharmacology attributes of drugs.
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PMID:Is there a place for drug combination strategies using clinical pharmacology attributes?--review of current trends in research. 1950 74

CYP2B6 is mainly expressed in the liver that has been thought historically to play an insignificant role in human drug metabolism. However, increased interest in this enzyme has been stimulated by the discovery of polymorphic and ethnic differences in CYP2B6 expression, identification of additional substrates for CYP2B6, and evidence for co-regulation with CYP3A4. This paper updates our knowledge about the structure, function, regulation and polymorphism of CYP2B6. CYP2B6 can metabolise approximately 8% of clinically used drugs (n > 60), including cyclophosphamide, ifosfamide, tamoxifen, ketamine, artemisinin, nevirapine, efavirenz, bupropion, sibutramine, and propofol. CYP2B6 is one of the CYP enzymes that bioactivate several procarcinogens and toxicants. This enzyme also metabolizes arachidonic acid, lauric acid, 17beta-estradiol, estrone, ethinylestradiol, and testosterone. Typical substrates of CYP2B6 are non-planar molecules, neutral or weakly basic, highly lipophilic with one or two hydrogen-bond acceptors. The crystal structure of CYP2B6 has not been resolved, while several pharmacophore and homology models of human CYP2B6 have been reported. Human CYP2B6 is closely regulated by constitutive androstane receptor (CAR/NR1I3) which can activate CYP2B6 expression upon ligand binding. Pregnane X receptor and glucocorticoid receptor also play a role in the regulation of CYP2B6. Induction of CYP2B6 may partially explain some clinical drug interactions observed. For example, coadministered carbamazepine decreases the systemic exposure of bupropion. There is a wide interindividual variability in the expression and activity of CYP2B6. Such a large variability is probably due to effects of genetic polymorphisms and exposure to drugs that are inducers or inhibitors of CYP2B6. To date, at least 28 allelic variants and some subvariants of CYP2B6 (*1B through *29) have been described and some of them have been shown to have important functional impact on drug clearance and drug response. For example, the efavirenz plasma levels in African-American subjects with the CYP2B6 homozygous 516T/T genotype are approximately 3-fold higher than individuals carrying the homozygous G/G genotype. The CYP2B6 516T/T genotype is associated with 1.7-fold greater plasma levels of nevirapine in HIV-infected patients. Smokers with the 1459C>T (R487C) variant of CYP2B6 may be more vulnerable to abstinence symptoms and relapse following treatment with bupropion as a smoking cessation agent. Further studies in the structure, function, regulation and polymorphism of CYP2B6 are warranted.
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PMID:Substrate specificity, regulation, and polymorphism of human cytochrome P450 2B6. 1970 27

Maraviroc is a potent selective CCR5 antagonist and is the first of this new class of oral agents to be approved for the treatment of CCR5-tropic HIV type-1. Maraviroc is extensively metabolized by CYP3A4, with renal clearance accounting for approximately 23% of total clearance. The half-life of maraviroc is approximately 16 h. Maraviroc does not inhibit any of the major CYP450 enzymes at clinically relevant doses and it has not shown any clinically relevant effects on plasma concentrations of other agents; hence, no dose adjustments of coadministered agents are required. Maraviroc exposure is altered by agents that modulate the activity of CYP3A4 and, in some circumstances, maraviroc dose adjustment is necessary. This article aims to review all pharmacokinetic and drug interaction data available for maraviroc, and to provide a comprehensive summary of the dose adjustment recommendations for maraviroc when coadministered with agents from all classes of antiretroviral therapy as well as other commonly coadministered agents.
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PMID:Maraviroc: pharmacokinetics and drug interactions. 1970 63

A patient with human immunodeficiency virus infection and end-stage renal disease received a renal transplant. At the time of surgery, the patient was on quadruple antiretroviral therapy (lamivudine, zidovudine, and amprenavir/ritonavir). Immunosuppression was initiated with basiliximab, corticosteroid, mycophenolate mofetil, and a single 0.5 mg dose of tacrolimus. In the following days, an increase in tacrolimus concentration was observed with a peak of 37 ng/mL. Tacrolimus half-life was 6.5 days and tacrolimus maintenance dose was 0.5 mg every 4 days. Eleven months later, the patient had developed Kaposi sarcoma. Tacrolimus was replaced by sirolimus (first dose 1 mg), and the patient was stabilized with 1.5 mg of sirolimus once a week. Increased tacrolimus half-life and increased dose interval of sirolimus and tacrolimus were due to CYP3A4/5 and/or P-glycoprotein inhibition by protease inhibitors. Close monitoring is required in the management of tacrolimus and sirolimus dosing regimens when combined with ritonavir boosted HIV-1 protease inhibitors.
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PMID:Effect of coadministered HIV-protease inhibitors on tacrolimus and sirolimus blood concentrations in a kidney transplant recipient. 1970 21

HIV infected patients often take at least three anti-HIV drugs together in Highly Active Antiretroviral Therapy (HAART) and/or Ritonavir-Boosted Protease Inhibitor Therapy (PI/r) to suppress the viral replications. The potential drug-drug interactions affect efficacy of anti-HIV treatment and major source of such interaction is competition for the drug metabolizing enzyme, cytochrome P450 (CYP). CYP3A4 isoform is the enzyme responsible for metabolism of currently available HIV-1 protease drugs. Hence administration of these drugs in HARRT or PI/r leads to increased toxicity and reduced efficacy in HIV treatment. We used computational molecular docking method to predict such interactions by which to compare experimentally measured metabolism of each HIV-1 protease drug. AutoDock 4.0 was used to carry out molecular docking of 10 HIV-protease drugs into CYP3A4 to explore sites of reaction and interaction energies (i.e., binding affinity) of the complexes. Arg105, Arg106, Ser119, Arg212, Ala370, Arg372, and Glu374 are identified as major drug binding residues, and consistent with previous data of site-directed mutagenesis, crystallography structure, modeling, and docking studies. In addition, our docking results suggested that phenylalanine clusters and heme are also participated in the binding to mediate drug oxidative metabolism. We have shown that HIV-1 protease drugs such as tipranavir, nelfinavir, lopinavir, and atazanavir differ in their binding modes on each other for metabolic clearance in CYP3A4, whereas ritonavir, amprenavir, indinavir, saquinavir, fosamprenavir, and darunavir share the same binding mode.
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PMID:Analysis of CYP3A4-HIV-1 protease drugs interactions by computational methods for Highly Active Antiretroviral Therapy in HIV/AIDS. 1993 78

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.
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PMID:Metabolism-mediated drug interactions associated with ritonavir-boosted tipranavir in mice. 2010 82

Atazanavir (ATV) is an HIV protease inhibitor (IP) with a high in vitro activity against HIV-1, that demonstrates a high additive activity in the presence of other antiretrovirals and a synergic activity with other PI. Oral absorption is greater than 68%, maximum concentration (C(max)) being reached approximately 2 to 3 h after its administration. Its absorption is dependent on gastric pH, its administration being recommended after meals. The pharmacokinetics (PK) of ATV are non-linear; that is to say, its plasma concentrations (C(p)) do not increase in proportion to the dose. ATV is approximately 86% bound to plasma proteins. Its entry into the cerebrospinal fluid, semen or genital secretions varies but is generally less than 10-20%. Its passage across the placenta, measured as the mean of the ratios between the C(p) in umbilical cord and maternal blood, is 0.13. ATV is metabolised by oxidation by cytochrome P450 enzymes, subsequently being eliminated by the bile duct in the free or glucuronide form (80%) and by the urine. ATV is a weak competitive inhibitor of CYP3A4 and a strong inhibitor of uridine diphosphate-glucuronosyltransferase 1A1, which is the cause of the frequent high plasma bilirubin after its administration and of its pharmacological interactions.
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PMID:[Pharmacology, pharmacokinetic features and interactions of atazanavir]. 2011 10

Lersivirine [UK-453,061, 5-((3,5-diethyl-1-(2-hydroxyethyl)(3,5-14C2)-1H-pyrazol-4-yl)oxy)benzene-1,3-dicarbonitrile] is a next-generation non-nucleoside reverse transcriptase inhibitor, with a unique binding interaction within the reverse transcriptase binding pocket. Lersivirine has shown antiviral activity and is well tolerated in HIV-infected and healthy subjects. This open-label, Phase I study investigated the absorption, metabolism, and excretion of a single oral 500-mg dose of [14C]lersivirine (parent drug) and characterized the plasma, fecal, and urinary radioactivity of lersivirine and its metabolites in four healthy male volunteers. Plasma C(max) for total radioactivity and unchanged lersivirine typically occurred between 0.5 and 3 h postdose. The majority of radioactivity was excreted in urine (approximately 80%) with the remainder excreted in the feces (approximately 20%). The blood/plasma ratio of total drug-derived radioactivity [area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUC(inf))] was 0.48, indicating that radioactive material was distributed predominantly into plasma. Lersivirine was extensively metabolized, primarily by UDP glucuronosyltransferase- and cytochrome P450-dependent pathways, with 22 metabolites being identified in this study. Analysis of precipitated plasma revealed that the lersivirine-glucuronide conjugate was the major circulating component (45% of total radioactivity), whereas unchanged lersivirine represented 13% of total plasma radioactivity. In vitro studies showed that UGT2B7 and CYP3A4 are responsible for the majority of lersivirine metabolism in humans.
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PMID:Excretion and metabolism of lersivirine (5-{[3,5-diethyl-1-(2-hydroxyethyl)(3,5-14C2)-1H-pyrazol-4-yl]oxy}benzene-1,3-dicarbonitrile), a next-generation non-nucleoside reverse transcriptase inhibitor, after administration of [14C]Lersivirine to healthy volunteers. 2012 96

Currently used combinations of anti-HIV drugs, known as Highly Active Antiretroviral Therapy (HAART), have considerably reduced the mortality in patients with AIDS. However, HAART medications such as efavirenz (EFV), atazanavir (ATV) and ritonavir (RTV) often cause adverse drug-drug interactions (DDIs) that result from changes in the expression and activity of drug metabolizing enzymes. Since EFV is most commonly used with ATV and RTV, the known CYP inhibitors, we evaluated the effects of combinations of these agents on the CYP3A4 induction by EFV. We determined the induction of CYP3A4 by EFV, RTV, ATV, EFV+RTV, EFV+ATV, EFV+RTV+ATV and rifampicin (RIF) employing primary human hepatocytes from 3 donors. Also, concentration dependent activation of human Pregnane X-receptor (hPXR) which is key transcriptional regulator of CYP3A4 by EFV, RIF and RTV was estimated in transiently transfected LS180 cells. CYP3A4 activity (testosterone-6beta-hydroxylation) was induced by EFV (3 fold) and RIF (4 fold), but was significantly suppressed in the presence of RTV and ATV. All treatments significantly induced the CYP3A4 transcripts (3-25 fold) as quantitated by RT-PCR. hPXR activation data in LS180 cells were consistent with the induction of transcripts and the estimated EC(50) values were 0.87 microM, 0.44 microM and 3.7 microM for RIF, RTV and EFV, respectively. However, in primary hepatocytes the net effect was suppression of EFV mediated CYP3A4 induction by RTV and ATV. This observation corresponds to the clinical observations of attenuated CYP3A4 induction by EFV induction in the presence of RTV and other protease inhibitors (PIs). Our results underscore the limitation of transcriptional activation assays in predicting the net outcome for compounds that exhibit complex interactions resulting from induction and inhibition of CYP enzymes.
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PMID:Impact of ritonavir, atazanavir and their combination on the CYP3A4 induction potential of efavirenz in primary human hepatocytes. 2020 76

The purpose of this study was to investigate the frequency of CYP2B6 polymorphisms and their influence on plasma concentrations of efavirenz and nevirapine in HIV-infected Chinese patients. After written informed consent, 159 patients were enrolled at Shanghai Public Health Clinical Center. Genotyping for 516 G>T, 785 A>G, 983 T>C, and 1459 T>C polymorphisms in CYP2B6, together with CYP3A4 -392 A>G, CYP3A5 6986 A>G, and ABCB1 (2677 G>T/A, 3435 C>T), were performed. Plasma efavirenz and nevirapine concentrations of 120 patients at steady state were assessed by high-performance liquid chromatography-mass spectrometry. The minor allele frequency for CYP2B6 516 G>T, 785 A>G, 983 T>C, and 1459 T>C was 0.16, 0.24, 0, and 0, respectively; and 0.07, 0.32, 0.15, and 0.35 for CYP3A4 -392 A>G, CYP3A5 6986 A>G, ABCB1 2677 G>T/A, and ABCB1 3435 C>T, respectively. Univariate analysis indicated associations between 516 G>T (P < 0.01) with efavirenz but not nevirapine plasma concentrations. None of other genetic variants was associated with plasma efavirenz or nevirapine concentrations. Although CYP2B6 516 G>T was associated with high plasma efavirenz concentrations, such an association was not evident with nevirapine in this Chinese patient population. CYP3A4 -392 A>G, CYP3A5 6986 A>G, and ABCB1 (2677 G>T/A, 3435 C>T) had no significant impact on plasma efavirenz or nevirapine concentrations.
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PMID:CYP2B6 polymorphism and nonnucleoside reverse transcriptase inhibitor plasma concentrations in Chinese HIV-infected patients. 2062 52

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