Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Since preclinical studies indicated that 3'-azido-3'-deoxythymidine (AZT, zidovudine, Retrovir, BW A509U), a potent anti-HIV agent, is not metabolized extensively in rats, rabbits, mice, guinea pigs, cats, or dogs, the extensive biotransformation of AZT observed in humans was not expected. On average, approximately 75% of an oral AZT dose is recovered in human urine as a single metabolite while only 14-18% of the dose is recovered unchanged. Ultraviolet, infrared, nuclear magnetic resonance, and mass spectra and enzymatic degradation characterized the isolated major metabolite as a 5'-O-glucuronide (3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine, GAZT), a very unique nucleoside metabolite. These observations suggest that UDP-glucuronosyltransferase (UDPGT), EC2.4.1.17, mediates the in vivo biotransformation of AZT to GAZT. Since glucuronidation is one of the major conjugation reactions involved in the metabolic conversion of xenobiotics to more polar, water-soluble metabolites, it is an important detoxification pathway in humans. Therefore, it is important to understand the enzymatic basis for the discrepancy between metabolism of AZT in laboratory mammals and humans. This is especially relevant in light of the use of laboratory mammals to predict the metabolism of novel pharmaceutical agents in humans. The study presented herein confirms that liver UDPGT does catalyze the glucuronidation of AZT and that the higher substrate efficiency of AZT with human enzyme compared to rodent enzyme may account for metabolic differences observed in vivo.
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PMID:Glucuronidation of 3'-azido-3'-deoxythymidine: human and rat enzyme specificity. 271 17

Zidovudine (3'-azido-3'-deoxythymidine [AZT]), an antiviral nucleoside analog effective in the treatment of human immunodeficiency virus infection, is primarily metabolized to an inactive glucuronide form, GAZT, via uridine-5'-diphospho-glucuronosyltransferase (UGT) enzymes. UGT enzymes exist as different isoforms, each exhibiting substrate specificity. Published clinical studies have shown that atovaquone, fluconazole, methadone, and valproic acid decreased GAZT formation, presumably due to UGT inhibition. The effect of these drugs on AZT glucuronidation was assessed in vitro by using human hepatic microsomes to begin understanding in vitro-in vivo correlations for UGT metabolism. The concentrations of each drug studied were equal to those reported with the usual clinical doses and at concentrations at least 10 times higher than would be expected with these doses. High-performance liquid chromatography was used to assess the respective metabolism and formation of AZT and GAZT. All four drugs exhibited concentration-dependent inhibition of AZT glucuronidation. The respective concentrations of atovaquone and methadone which caused 50% inhibition of GAZT were > 100 and 8 micrograms/ml, well above their usual clinical concentrations. Fluconazole and valproic acid exhibited 50% inhibition of GAZT at 50 and 100 micrograms/ml, which are within the clinical ranges of 10 to 100 and 50 to 100 micrograms/ml, respectively. These data suggest that inhibition of AZT glucuronidation may be more clinically significant with concomitant fluconazole and valproic acid. Factors such as inter- and intraindividual pharmacokinetic variability and changes in AZT intracellular concentrations should be considered as other mechanisms responsible for changes in AZT pharmacokinetics with concomitant therapies.
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PMID:Glucuronidation of 3'-azido-3'-deoxythymidine (zidovudine) by human liver microsomes: relevance to clinical pharmacokinetic interactions with atovaquone, fluconazole, methadone, and valproic acid. 966 Sep 89

Indinavir is a viral protease inhibitor used for the treatment of HIV infection. Unconjugated hyperbilirubinemia develops in up to 25% of patients receiving indinavir, prompting drug discontinuation and further clinical evaluation in some instances. We postulated that this side-effect is due to indinavir-mediated impairment of bilirubin UDP-glucuronosyltransferase (UGT) activity and would be most pronounced in individuals with reduced hepatic enzyme levels, as occurs in approximately 10% of the population manifesting Gilbert's syndrome. This hypothesis was tested in vitro, in the Gunn rat model of UGT deficiency, and in HIV-infected patients with and without the Gilbert's polymorphism. Indinavir was found to competitively inhibit UGT enzymatic activity (K(I) = 183 microM) while concomitantly inducing hepatic bilirubin UGT mRNA and protein expression. Although oral indinavir increased plasma bilirubin levels in wild-type and heterozygous Gunn rats, the mean rise was significantly greater in the latter group of animals. Similarly, serum bilirubin increased by a mean of 0.34 mg/dl in indinavir-treated HIV patients lacking the Gilbert's polymorphism versus 1.45 mg/dl in those who were either heterozygous or homozygous for the mutant allele. Whereas saquinavir also competitively inhibits UGT activity, this drug has not been associated with hyperbilirubinemia, most likely because of the higher K(I) (360 microM) and substantially lower therapeutic levels as compared with indinavir. Taken together, these findings indicate that elevations in serum-unconjugated bilirubin associated with indinavir treatment result from direct inhibition of bilirubin-conjugating activity.
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PMID:Mechanism of indinavir-induced hyperbilirubinemia. 1198 77

PA-457 [3-O-(3',3'-dimethylsuccinyl)-betulinic acid] represents a new class of anti-HIV drug candidates termed maturation inhibitors. After oral administration to rats, PA-457 was metabolized to several glucuronide conjugates and mainly eliminated into rat bile. Liquid chromatography-electrospray ionization-mass spectrometry analysis showed that the glucuronidation products of PA-457 were acyl glucuronides including one di-glucuronide, di-PA-457G, and two mono-glucuronides, referred to as mono-PA-457G (I) and mono-PA-457G (II), respectively. In-source fragmentation of MS spectra supported the conclusion that mono-PA-457G (I) was glucuronidated at the C-28 carboxyl of PA-457, whereas mono-PA-457G (II) was conjugated at the dimethylsuccinic acid side chain of the C-3 position. Quantification demonstrated that the predominant glucuronide of PA-457 in rat bile was mono-PA-457G (I) with lower amounts of mono-PA-457G (II) and di-PA-457G. In vitro stability indicated that the mono-acyl glucuronides of PA-457 were not degraded after incubation with 0.1 M phosphate buffer (pH 4, 7.4 and 9), plasma (human, rat, and mouse), and UDP-glucuronosyltransferase reaction media (without uridine 5'-diphosphoglucuronic acid) with microsomes (human, rat, and mouse liver microsomes), respectively, whereas the minor diglucuronide was unstable in rodent liver microsomes. All glucuronides of PA-457 could be hydrolyzed both by beta-glucuronidase and alkaline (1 M NaOH). Minor putative acyl migration products were slowly formed at pH 9, suggesting that the acyl glucuronides of PA-457 have relatively high in vitro stability.
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PMID:Structural characterization of anti-HIV drug candidate PA-457 [3-O-(3',3'-dimethylsuccinyl)-betulinic acid] and its acyl glucuronides in rat bile and evaluation of in vitro stability in human and animal liver microsomes and plasma. 1675 Dec 62

Abacavir is a carbocyclic 2'-deoxyguanosine nucleoside reverse transcriptase inhibitor that is used as either a 600-mg once-daily or 300-mg twice-daily regimen exclusively in the treatment of HIV infection. Abacavir is rapidly absorbed after oral administration, with peak concentrations occurring 0.63-1 hour after dosing. The absolute bioavailability of abacavir is approximately 83%. Abacavir pharmacokinetics are linear and dose-proportional over the range of 300-1200 mg/day. To date, one study has assessed the steady-state pharmacokinetics of abacavir following a 600-mg once-daily regimen, and reported a geometric mean steady-state abacavir peak concentration of 3.85 microg/mL. Although this concentration is higher than the steady-state abacavir peak concentration reported following a 300-mg twice-daily regimen (0.88-3.19 microg/mL, depending on the study), the geometric mean steady-state abacavir exposure over 24 hours was similar following these regimens. Coadministration with food has no significant effect on abacavir exposure; therefore, abacavir may be administered with or without food.The apparent volume of distribution of abacavir after intravenous administration is approximately 0.86 +/- 0.15 L/kg, suggesting that abacavir is distributed to extravascular spaces. Binding to plasma proteins is about 50% and is independent of the plasma abacavir concentration. Abacavir is extensively metabolized by the liver; less than 2% is excreted as unchanged drug in the urine. Abacavir is primarily metabolized via two pathways, uridine diphosphate glucuronyltransferase and alcohol dehydrogenase, resulting in the inactive glucuronide metabolite (361W94, ~36% of the dose recovered in the urine) and the inactive carboxylate metabolite (2269W93, approximately 30% of the dose recovered in the urine). The remaining 15% of abacavir equivalents found in the urine are minor metabolites, each less than 2% of the total dose. Faecal elimination accounts for about 16% of the dose. The terminal elimination half-life of abacavir is approximately 1.5 hours. The antiviral effect of abacavir is due to its intracellular anabolite, carbovir-triphosphate (CBV-TP). When assessed by validated high-performance liquid chromatography electrospray ionization tandem mass spectrometry, CBV-TP has been shown to have a long elimination half-life (>20 hours), supporting once-daily dosing. The mean CBV-TP trough concentrations do not differ following abacavir 600-mg once-daily and 300-mg twice-daily regimens. Limited data are available for abacavir in subjects with renal dysfunction or hepatic impairment. Abacavir pharmacokinetics in HIV-infected subjects with end-stage renal disease were found to be no different from those observed in healthy adults; this finding was consistent with the kidney being a minor route of abacavir elimination. A study of abacavir pharmacokinetics in hepatically impaired adults (Child-Pugh score of 5-6) showed that the abacavir area under the plasma concentration-time curve and elimination half-life were 89% and 58% greater, respectively, suggesting that the daily dose of abacavir should be reduced in patients with mild hepatic impairment (Child-Pugh score of 5-6). Abacavir pharmacokinetics have not been studied in patients with higher Child-Pugh scores. Abacavir is not significantly metabolized by cytochrome P450 (CYP) enzymes, nor does it inhibit these enzymes. Therefore, clinically significant drug interactions between abacavir and drugs metabolized by CYP enzymes are unlikely. The potential for drug interactions is no different when abacavir is used as a once-daily regimen versus a twice-daily regimen. No clinically significant drug interactions have been observed between recommended doses of abacavir and lamivudine, zidovudine, alcohol (ethanol) or methadone.
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PMID:A review of the pharmacokinetics of abacavir. 1847 71

Raltegravir is an HIV integrase inhibitor that is metabolized through glucuronidation by uridine diphosphate glucuronosyltransferase 1A1, and its use is anticipated in combination with atazanavir (a uridine diphosphate glucuronosyltransferase 1A1 inhibitor). Two pharmacokinetic studies of healthy subjects assessed the effect of multiple-dose atazanavir or ritonavir-boosted atazanavir on raltegravir levels in plasma. Atazanavir and atazanavir plus ritonavir modestly increase plasma levels of raltegravir.
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PMID:Atazanavir modestly increases plasma levels of raltegravir in healthy subjects. 1851 46

Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) developed for the treatment of HIV-1 infection. It has a high genetic barrier to the emergence of viral resistance, and maintains its antiviral activity in the presence of common NNRTI mutations. The pharmacokinetics of etravirine in HIV-infected patients at the recommended dosage of 200 mg twice daily demonstrates moderate intersubject variability and no time dependency. Due to substantially lower exposures when taken on an empty stomach, etravirine should be administered following a meal. The drug is highly protein bound (99.9%) to albumin and alpha(1)-acid glycoprotein and shows a relatively long elimination half-life of 30-40 hours. Etravirine is metabolized by cytochrome P450 (CYP) 3A, 2C9 and 2C19; the metabolites are subsequently glucuronidated by uridine diphosphate glucuronosyltransferase. Renal elimination of etravirine is negligible. Etravirine has the potential for interactions by inducing CYP3A and inhibiting CYP2C9 and 2C19; it is a mild inhibitor of P-glycoprotein but not a substrate. The drug interaction profile of etravirine has been well characterized and is manageable. No dosage adjustments are needed in patients with renal impairment or mild to moderate hepatic impairment. Race, sex, bodyweight and age do not affect the pharmacokinetics of etravirine. In the two phase III trials DUET-1 and DUET-2, no relationship was demonstrated between the pharmacokinetics of etravirine and the primary efficacy endpoint of viral load below 50 copies/mL or the safety profile of etravirine.
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PMID:Clinical pharmacokinetics and pharmacodynamics of etravirine. 1972 91

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

Highly active antiretroviral therapy (HAART) has increased the survival of HIV-infected patients. However, adverse effects play a major role in adherence to HAART. Some protease inhibitors (mainly atazanavir and indinavir) act as inhibitors of uridine diphosphate-glucuronosyltransferase (UGT1A1), the enzyme responsible for hepatic conjugation of bilirubin. Variations in the promoter region of the UGT1A1 gene (UGT1A1*28, rs8175347) can influence bilirubin plasma levels, modulating the susceptibility to hyperbilirubinemia. Aiming to analyze the association between UGT1A1*28 allele and hyperbilirubinemia in individuals exposed to HAART, we evaluated 375 HIV-positive individuals on antiretroviral therapy. Individuals carrying the UGT1A1*28 allele had a higher risk of developing severe hyperbilirubinemia [prevalence ratio (PR)=2.43, 95% confidence interval (CI) 1.08-5.45, p=0.032] as well as atazanavir users (PR=7.72, 95% CI=3.14-18.98, p<0.001). This is the first description of such an association in Brazilian HIV patients, which shows that in African-American and Euroamerican HAART users, the UGT1A1*28 allele also predisposes to severe hyperbilirubinemia, especially in those exposed to atazanavir.
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PMID:Short communication: UGT1A1*28 variant allele is a predictor of severe hyperbilirubinemia in HIV-infected patients on HAART in southern Brazil. 2205 Jul 34


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