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: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pathological disorders of the liver were shown to be associated with an impairment of hepatic drug metabolism mediated in part by growth factors. Augmenter of liver regeneration (ALR) is a novel liver-specific hepatotrophic growth factor, whereas its action on cytochrome P450 (P450) metabolism is completely unknown. Application of ALR to primary human hepatocytes in vitro reduced P450 isoenzyme activities (1A2 and 2A6) in a dose-dependent manner. Time-course analysis revealed that the maximal inhibitory effect was reached after 24 to 72 h of exposure with 50 nM ALR. The reduction of basal activities upon ALR treatment was 35% for CYP1A2, 56% for CYP2A6, 18% for CYP2B6, and 45% for CYP2E1. Additionally, after induction of P450 with specific inducers, ALR revealed an inhibitory effect on the isoenzyme activities (CYP1A2, 41%; CYP2B6, 35%). Investigations of protein and mRNA expression of basal and induced CYP1A2 and CYP3A4 after ALR treatment by Western blotting and real-time reverse transcriptase-polymerase chain reaction, respectively, suggest a regulation on the transcriptional level. Furthermore, ALR treatment increased nuclear factor kB activity and reduced constitutive androstane receptor but not pregnane X receptor or aryl hydrocarbon receptor expression. In contrast, ALR revealed no effects on phase II reactions (glutathione/oxidized glutathione, UDP-glucuronyltransferase conjugation). Our results indicate that ALR, as a member of hepatotrophic factors, down-regulates basal and induced P450 in human liver and therefore cross-links growth signals to regulation of hepatic metabolism. These findings further imply a possible role of ALR in drug interactions during impaired hepatic function, whereas liver regeneration is triggered.
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PMID:Repression of cytochrome P450 activity in human hepatocytes in vitro by a novel hepatotrophic factor, augmenter of liver regeneration. 1621 78

Fosamprenavir is one of the most recently approved HIV-1 protease inhibitors (PIs) and offers reductions in pill number and pill size, and omits the need for food and fluid requirements associated with the earlier-approved HIV-1 PIs. Three fosamprenavir dosage regimens are approved by the US FDA for the treatment of HIV-1 PI-naive patients, including fosamprenavir 1,400 mg twice daily, fosamprenavir 1,400 mg once daily plus ritonavir 200mg once daily, and fosamprenavir 700 mg twice daily plus ritonavir 100mg twice daily. Coadministration of fosamprenavir with ritonavir significantly increases plasma amprenavir exposure. The fosamprenavir 700 mg twice daily plus ritonavir 100mg twice daily regimen maintains the highest plasma amprenavir concentrations throughout the dosing interval; this is the only approved regimen for the treatment of HIV-1 PI-experienced patients and is the only regimen approved in the European Union. Fosamprenavir is the phosphate ester prodrug of the HIV-1 PI amprenavir, and is rapidly and extensively converted to amprenavir after oral administration. Plasma amprenavir concentrations are quantifiable within 15 minutes of dosing and peak at 1.5-2 hours after fosamprenavir dosing. Food does not affect the absorption of amprenavir following administration of the fosamprenavir tablet formulation; therefore, fosamprenavir tablets may be administered without regard to food intake. Amprenavir has a large volume of distribution, is 90% bound to plasma proteins and is a substrate of P-glycoprotein. With <1% of a dose excreted in urine, the renal route is not an important elimination pathway, while the principal route of amprenavir elimination is hepatic metabolism by cytochrome P450 (CYP) 3A4. Amprenavir is also an inhibitor and inducer of CYP3A4. Furthermore, fosamprenavir is commonly administered in combination with low-dose ritonavir, which is also extensively metabolised by CYP3A4, and is a more potent CYP3A4 inhibitor than amprenavir. This potent CYP3A4 inhibition contraindicates the coadministration of certain CYP3A4 substrates and requires others to be co-administered with caution. However, fosamprenavir can be co-administered with many other antiretroviral agents, including drugs of the nucleoside/nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and HIV entry inhibitor classes. Coadministration with other HIV-1 PIs continues to be studied.The extensive fosamprenavir and amprenavir clinical drug interaction information provides guidance on how to co-administer fosamprenavir and fosamprenavir plus ritonavir with many other commonly co-prescribed medications, such as gastric acid suppressants, HMG-CoA reductase inhibitors, antibacterials and antifungal agents.
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PMID:Fosamprenavir : clinical pharmacokinetics and drug interactions of the amprenavir prodrug. 1648 15

A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. Nelfinavir pharmacokinetics was described by a one-compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Mean pharmacokinetic estimates and the corresponding intersubject percent variabilities for a nonpregnant woman were the following: absorption rate, 0.83 h(-1); absorption lag time, 0.85 h; apparent nelfinavir elimination clearance (CL(10)/F), 35.5 liters/h (50%); apparent volume of distribution (V/F), 596 liters (118%); apparent formation clearance to M8 (CL(1M)/F), 0.65 liters/h (69%); and M8 elimination rate constant (k(M0)), 3.3 h(-1) (59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h(-1)) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery.
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PMID:Pregnancy-related effects on nelfinavir-M8 pharmacokinetics: a population study with 133 women. 1672 69

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

Cytochrome P450 (P450) induction may have considerable implications for drug therapy. Therefore, understanding the induction potential of a new chemical entity at an early stage in discovery is crucial to reduce the risk of failure in the clinic and help the identification of noninducing chemical structures. Availability of human viable tissue often limits evaluation of induction potential in human hepatocytes. A solution is to increase the time period during which the hepatocytes remain viable. In this study we have investigated the induction of several P450 isozymes in long-term cultured hepatocytes compared with short-term cultured hepatocytes from the same individuals. Short- and long-term cultured primary hepatocytes isolated from each individual were cultured in a 96-well format and treated for 24 h with a range of prototypical P450 inducers and Merck Research Laboratories compounds. CYP3A4, 1A1, 1A2, 2B6, and 2C9 mRNA levels were measured using quantitative real-time reverse transcriptase-polymerase chain reaction (TaqMan) from the same cultured hepatocyte wells. CYP3A4, 1A1, 1A2, 2B6, and 2C9 were shown to be inducible in long-term cultured hepatocytes. The -fold induction varied between donors, and between short- and long-term cultured hepatocytes from the same donor. However, this variability can be controlled by normalizing data from each hepatocyte preparation to a positive control. The use of long-term cultured hepatocytes on 96-well plates has proven to be sensitive, robust, and convenient for assessing P450 induction potential of new compound entities during the drug discovery process.
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PMID:Utility of long-term cultured human hepatocytes as an in vitro model for cytochrome p450 induction. 1709 7

Our objective was to investigate the expression of different cytochromes P450 3A (CYP3A4, CYP3A5, and CYP3A7) and P-glycoprotein (ABCB1) genes along the human large intestine in paired tumour and normal samples. Real-time reverse transcriptase-polymerase chain reaction was used to measure CYP3A4-, CYP3A5-, CYP3A7- and ABCB1-specific mRNA expression, and Western blot analysis was used to measure membrane protein levels of CYP3A4/7, CYP3A5 and P-glycoprotein. Levels of mRNA and membrane protein fractions in the large intestine were compared with those of normal human liver. The mRNA expressions of CYP3A4, CYP3A5, CYP3A7 and ABCB1 in the large intestine were found to be highly variable, but overall the levels were significantly lower than those measured in liver (P < 0.0001, P < 0.001, P < 0.0001 and P < 0.01, respectively). At the membrane protein level, CYP3A4/7 was detected in all large intestine samples examined and the levels were substantially higher than those of the liver (P < 0.01). Although expression of CYP3A5 was detected in all large intestine samples, in most the levels were too low to allow quantification. P-glycoprotein was readily detected at levels slightly higher than those of liver (P < 0.05). Comparison between paired samples of normal and tumour in large intestine showed no significant differences in either the mRNA or membrane protein levels of these genes. In conclusion, this work suggests a potential role of the large intestine in the absorption and metabolism of xenobiotics and nutrients and no difference in the CYP3A and P-glycoprotein membrane protein fractions and mRNA expression between normal and tumour tissues.
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PMID:Expression of cytochromes P450 3A and P-glycoprotein in human large intestine in paired tumour and normal samples. 1737 28

In our study, we tested the hypothesis whether valproic acid (VPA) in therapeutic concentrations has potential to affect expression of CYP3A4 and MDR1 via constitutive androstane receptor (CAR) and pregnane X receptor (PXR) pathways. Interaction of VPA with CAR and PXR nuclear receptors was studied using luciferase reporter assays, real-time reverse transcriptase polymerase chain reaction (RT-PCR), electrophoretic mobility shift assay (EMSA), and analysis of CYP3A4 catalytic activity. Using transient transfection reporter assays in HepG2 cells, VPA was recognized to activate CYP3A4 promoter via CAR and PXR pathways. By contrast, a significant effect of VPA on MDR1 promoter activation was observed only in CAR-cotransfected HepG2 cells. These data well correlated with up-regulation of CYP3A4 and MDR1 mRNAs analyzed by real-time RT-PCR in cells transfected with expression vectors encoding CAR or PXR and treated with VPA. In addition, VPA significantly up-regulated CYP3A4 mRNA in primary hepatocytes and augmented the effect of rifampicin. EMSA experiments showed VPA-mediated augmentation of CAR/retinoid X receptor alpha heterodimer binding to direct repeat 3 (DR3) and DR4 responsive elements of CYP3A4 and MDR1 genes, respectively. Finally, analysis of specific CYP3A4 catalytic activity revealed its significant increase in VPA-treated LS174T cells transfected with PXR. In conclusion, we provide novel insight into the mechanism by which VPA affects gene expression of CYP3A4 and MDR1 genes. Our results demonstrate that VPA has potential to up-regulate CYP3A4 and MDR1 through direct activation of CAR and/or PXR pathways. Furthermore, we suggest that VPA synergistically augments the effect of rifampicin in transactivation of CYP3A4 in primary human hepatocytes.
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PMID:Valproic acid induces CYP3A4 and MDR1 gene expression by activation of constitutive androstane receptor and pregnane X receptor pathways. 1739 93

A randomized, placebo-controlled (with respect to voriconazole), 2-period, multiple-dose intragroup fixed-dose sequence study was conducted in 34 healthy male subjects to evaluate the interactions between voriconazole (triazole antifungal agent) and efavirenz (reverse transcriptase inhibitor). In period 1, subjects received 200 mg twice-daily (bid) voriconazole (n = 17) or placebo (n = 17) for 3 days (400-mg bid loading doses on day 1). In period 2, following a 7-day washout, subjects received 400 mg once-daily (qd) efavirenz alone for 10 days (days 11-20). Then efavirenz was coadministered with 200 mg bid voriconazole or placebo for the next 9 days (days 21-29). Serial plasma voriconazole and efavirenz concentrations were measured on days 3, 19, and 29, and the safety data were collected throughout the study. The 400-mg qd efavirenz dose substantially reduced the steady-state mean voriconazole area under the curve over the dosing interval (AUC0-12) by 80% (90% confidence interval [CI], 75%-84%) and peak concentration (Cmax) by 66% (90% CI, 57%-73%). The decrease in voriconazole exposure during coadministration is probably mainly due to the induction of CYP2C19 and CYP2C9 by efavirenz. The 200 mg bid voriconazole increased the steady-state mean AUC0-24 and Cmax of efavirenz by 43% (90% CI, 36%-51%) and 37% (90% CI, 29%-46%), respectively. The increase in efavirenz exposure during coadministration is probably due to the inhibition of CYP3A4 by voriconazole. Coadministration of 200 mg bid voriconazole with 400 mg (or higher) qd efavirenz is contraindicated due to the clinically significant effect of efavirenz on voriconazole pharmacokinetics.
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PMID:Pharmacokinetic interaction between voriconazole and efavirenz at steady state in healthy male subjects. 1802 25

The success of antiretroviral therapy leads to a chronification of HIV-infection resulting in a decline of lethality. The lifelong intake of antiinfectives, though, may result in drug side effects with clinical dental implications. Despite fundamental cellular alterations, including prolonged hemorrhage following surgical interventions, antiretrovirals of all classes, of protease inhibitors, (non-nucleoside) reverse transcriptase inhibitors and of fusion inhibitors may promote oral manifestions like oral ulcera, dysgeusia, salivary gland disorders, papilloma, (peri)oral paresthesia or aphtous stomatitis. Due to inhibitory effects especially of protease inhibitors of cy tochrome P450-isoenzyme CYP3A4 therapeutical interactions with psychotropics/sedatives, antifungal agents, corticoids and intiinfectives, particularly metronidazole, may raise. The application and prescription of systemically metabolized adjuvant drugs as well as the monitoring of the possible progression of HIV infection is a key task in the oral health care of HIV-seropositive patients calling for a close medical coordination of therapeutical interventions.
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PMID:[Implications of antiretroviral therapy in oral medicine--a review of literature]. 1822 98

Highly active antiretroviral therapy (HAART) for human immunodeficiency virus (HIV) has resulted in significant morbidity and mortality reductions. Lifelong antiretroviral therapy must be incorporated into each patient's medical regimen. Patients with HIV may also have simultaneous chronic medical conditions, resulting in the possibility of complex drug-drug interactions. We report a possible drug-drug interaction between HAART and warfarin in two patients, as assessed by the Naranjo adverse drug reaction probability scale and the Drug Interaction probability scale. Both patients' pharmacotherapy regimens included a nonnucleoside reverse transcriptase inhibitor (NNRTI), nevirapine, or a protease inhibitor, nelfinavir or lopinavir-ritonavir, and two nucleoside analogs. In both patients, high warfarin doses were required to maintain therapeutic international normalized ratios (INRs). Warfarin has two enantiomers, R-and S-warfarin, which are substrates primarily of cytochrome P450 (CYP) 3A4 (R-warfarin), CYP1A2 (R-warfarin), and CYP2C9 (S-warfarin). Protease inhibitors and NNRTIs have variable effects on CYP: induction, inhibition, or mixed. The increased warfarin doses required in these two patients may have been caused by induction of CYP3A4 by nevirapine, CYP2C9 by nelfinavir, or CYP2C9 by lopinavir-ritonavir. Thus, practitioners should prudently monitor INRs in patients receiving warfarin with concomitant HAART that includes either a protease inhibitor or an NNRTI.
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PMID:Possible antiretroviral therapy-warfarin drug interaction. 1857 10


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