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

---

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

Despite the established impact of highly active antiretroviral therapy (HAART) in reducing HIV-related morbidity and mortality, malignancy remains an important cause of death. Patients who receive the combination of cancer chemotherapy and HAART may achieve better response rates and higher rates of survival than patients who receive antineoplastic therapy alone. However, the likelihood of drug interactions with combined therapy is high, since protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are substrates and potent inhibitors or inducers of the cytochrome P450 (CYP) system. Since many antineoplastic drugs are also metabolised by the CYP system, coadministration with HAART could result in either drug accumulation and possible toxicity, or decreased efficacy of one or both classes of drugs. Although formal, prospective pharmacokinetic interaction studies are not available in most instances, it is possible to infer the nature of drug interactions based on the metabolic fates of these agents. Paclitaxel and docetaxel are both metabolised by the CYP system, although differences exist in the nature of the isoenzymes involved. Case reports describing adverse consequences of concomitant taxane-antiretroviral therapy exist. Although other confounding factors may have been present, these cases serve as reminders of the vigilant monitoring necessary when taxanes and HAART are coadministered. Similarly, vinca alkaloids are substrates of CYP3A4 and are, thus, vulnerable to PI- or NNRTI-mediated changes in their pharmacokinetics. Interactions with the alkylating agents cyclophosphamide and ifosfamide are complicated as a result of the involvement of the CYP3A4 and CYP2B6 isoenzymes in both the metabolic activation of these drugs and the generation of potentially neurotoxic metabolites. Existing data regarding the metabolic fate of the anthracyclines doxorubicin and daunorubicin suggest that clinically detrimental interactions would not be expected with coadministered HAART. Commonly used endocrine therapies are largely substrates of the CYP system and may, therefore, be amenable to modulation by concomitant HAART. In addition, tamoxifen itself has been associated with reduced concentrations of both anastrozole and letrozole, raising the concern that similar inducing properties may adversely affect the outcome of PI- or NNRTI-based therapy. Similarly, dexamethasone is both a substrate and concentration-dependent inducer of CYP3A4; enhanced corticosteroid pharmacodynamics may result with CYP3A4 inhibitors, while the efficacy of concomitant HAART may be compromised with prolonged dexamethasone coadministration. Since PIs and NNRTIs may also induce or inhibit the expression of P-glycoprotein, the potential for additional interactions to arise via modulation of this transporter also exists. Further research delineating the combined safety and pharmacokinetics of antiretrovirals and antineoplastic therapy is necessary.
...
PMID:Interactions between antiretrovirals and antineoplastic drug therapy. 1565 94

P-glycoprotein (PGP) encoded by the Mdr1 gene mediates the excretion of drugs in organs such as the liver and kidney. Inflammation has been shown to suppress the expression and activity of PGP in rodent liver, thus potentially altering the pharmacokinetics of drugs that are substrates of PGP. Here we examined the effect of endotoxin (lipopolysaccharide; LPS)-induced inflammation on the disposition of the PGP substrate doxorubicin (DOX) in the mouse. Male CD-1 mice received 5 mg/kg LPS intraperitoneally. DOX (5 mg/kg) was administered intravenously 24 h after LPS treatment. The time course of DOX levels in plasma, urine, bile, and tissues was analyzed by high performance liquid chromatography. PGP protein and mRNA expression in liver and kidney was measured using Western blots and reverse transcriptase polymerase chain reaction. As compared to controls, LPS-treated mice exhibited a significant decrease (50%) in biliary clearance and 3-fold increased renal clearance of DOX. These changes were associated with strongly reduced PGP protein levels (30% controls, p < 0.05) in the liver and increased PGP levels in the kidney (140% controls, p < 0.05). Hepatic mRNA levels of all Mdr isoforms were reduced in LPS-treated mice, whereas renal Mdr1b levels were increased. In LPS-treated mice, we also measured an increased area under the plasma concentration-time curve and reduced systemic clearance of DOX, as well as a 2- to 5-fold increase in the urinary excretion of the doxorubicin and doxorubicinol aglycones. Our data suggest that endotoxin-induced inflammation in mice causes differential regulation of PGP in liver and kidney, thereby altering the clearance profile of DOX.
...
PMID:Impact of endotoxin-induced changes in P-glycoprotein expression on disposition of doxorubicin in mice. 1577 72

Treatment of HIV-1-infected patients with anti-retroviral agents is not always successful due to the emergence of resistant HIV-1 mutants with reduced susceptibility to the agents. However, factors other than viral mutation may also contribute to treatment failure. It has been demonstrated that the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp/ABCB1) is a key determinant of oral bioavailability of HIV-1 protease inhibitors and their penetration of the central nervous system. More recently, we have found that the expression of breast cancer resistance protein (BCRP/ABCG2) in a CD4+ T-cell line confers cellular resistance to nucleoside reverse transcriptase inhibitors (NRTIs). The anti-HIV-1 activity of the NRTI zidovudine (AZT) was significantly diminished through the reduction of its metabolite levels in MT-4 cells which express high levels of BCRP. Moreover, the BCRP-specific inhibitor fumitremorgin C could completely restore the cytotoxicity of AZT and intracellular levels of its metabolites in BCRP-expressing cells. Thus, BCRP is considered to be a cellular factor that modulates the anti-HIV-1 activity of NRTIs.
...
PMID:The role of breast cancer resistance protein (BCRP/ABCG2) in cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. 1613 May 19

Pharmacogenomic studies are contributing to our understanding of interindividual differences in response to antiretroviral drugs. Genetic polymorphism in major histocompatibility complex genes predict likelihood of hypersensitivity reactions in persons prescribed abacavir, and perhaps nevirapine. Recent studies have shown that a polymorphisms in the CYP2B6 gene is associated with higher plasma efavirenz concentrations and increased efavirenz central nervous system side effects. Polymorphisms in the MDR1 gene encoding the drug pump, P-glycoprotein, may predict nevirapine-associated hepatoxicity and long-term virologic response to efavirenz. CYP2C19 polymorphisms predict nelfinavir plasma levels and, possibly, risk of virologic failure on this drug. A European mitochondrial haplogroup may predict increased risk of peripheral neuropathy associated with nucleoside reverse transcriptase inhibitors. Expansion and refinement of knowledge regarding associations between human genetics and response to antiretroviral drugs may ultimately permit individualization of therapy based on genotyping. This article summarizes a presentation on HIV therapeutics and pharmacogenomics by David W. Haas, MD, at the International AIDS Society-USA course in Atlanta in March 2005.
...
PMID:Will pharmacogenomic discoveries improve HIV therapeutics? 1617 Feb 25

Most reverse transcriptase and protease inhibitors used in highly active antiretroviral therapy for treating human immunodeficiency virus (HIV) infections exhibit poor penetration into the brain, raising the concern that the brain may be a sanctuary site for the development of resistant HIV variants. This study explores the relationship between the dose and plasma and brain concentrations of zosuquidar and the effect of this selective P-glycoprotein inhibitor on central nervous system penetration of the HIV protease inhibitor nelfinavir maintained at steady state by intravenous infusions in rats. Nelfinavir was infused (10 mg/kg/h) for up to 10 h with or without concurrent administration of an intravenous bolus dose of 2, 6, or 20 mg/kg zosuquidar given at 4 h. Brain tissue and plasma were analyzed for both drug concentrations. Brain tissue/plasma nelfinavir concentration ratios (uncorrected for the vascular contribution) increased nonlinearly with zosuquidar dose from 0.06 +/- 0.03 in the absence of zosuquidar and 0.09 +/- 0.02 between 2 and 6 h after 2 mg/kg zosuquidar to 0.85 +/- 0.19 after 6 mg/kg and 1.58 +/- 0.67 after 20 mg/kg zosuquidar. Zosuquidar brain tissue/plasma concentration ratios exhibited a similar abrupt increase from 2.8 +/- 0.3 after a 2 mg/kg dose to approximately 15 after the 6 and 20 mg/kg doses. The apparent threshold in the plasma concentration of zosuquidar necessary to produce significant enhancement in brain uptake of nelfinavir appears to be close to the plasma concentrations associated with the maximum tolerated dose reported in the literature after repeated dosing of zosuquidar in patients.
...
PMID:Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats. 1643 46

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.
...
PMID:Fosamprenavir : clinical pharmacokinetics and drug interactions of the amprenavir prodrug. 1648 15

Resistance to anticancer drugs is often mediated by the overexpression of P-glycoprotein encoded by the multi-drug resistance (MDR1) gene. The nuclear receptor, steroid and xenobiotic receptor (SXR), is one of the key transcriptional regulators of MDR1 gene expression. A variety of xenobiotics bind to SXR, and stimulate transcription on xenobiotic-response elements (XREs), located in the MDR1 gene promoter. Diethylhexyl phthalate (DEHP) is widely used as a plasticizer for polyvinyl chloride (PVC) medical devices. Previous studies have shown that a significant amount of DEHP leaches from PVC infusion bags and lines during interventions, such as total parenteral nutrition, blood transfusion, and cancer chemotherapy. Thus, the leaching of DEHP during parenteral chemotherapy for cancer patients may facilitate MDR1 expression in various tissues, including cancer cells, which may promote drug resistance. To examine such a hypothesis, the effect of DEHP on SXR-mediated transcription of the MDR1 gene was studied in the human colon adenocarcinoma-derived cell line, LS174T cells, which endogenously express SXR. DEHP increased the SXR-mediated transcription of the MDR1 gene in luciferase-reporter assays. The induction by DEHP was abrogated when a reporter plasmid containing mutated DR+4 motif in the XRE was used. In a mammalian two-hybrid assay, DEHP recruited steroid receptor co-activator-1 to the ligand-binding domain of SXR. Finally, using real-time reverse transcriptase-PCR, we showed that DEHP increased MDR1 gene expression in a dose-dependent manner. We conclude that DEHP is an inducer of the MDR1 gene in this cell line. As such, the leaching of DEHP from the PVC medical devices may influence the MDR1 expression, which may induce resistance to drugs in certain populations of cancer cells.
...
PMID:The endocrine disrupting chemical, diethylhexyl phthalate, activates MDR1 gene expression in human colon cancer LS174T cells. 1700 90

Many drug interactions with drugs used for the therapy of human immunodeficiency virus (HIV) occur at the level of different cytochrome P450 isozymes. Increasing evidence suggests that antiretrovirals may also modify activity and expression of active drug transport systems. Such interactions may alter drug absorption, elimination, and also drug distribution and reach clinical importance if thereby access to the target site is affected. Beyond P-glycoprotein, the family of multidrug resistance-related proteins (MRP/ABCC) substantially contributes to the elimination of numerous drugs and their metabolites. Because the interaction of MRPs with non-HIV protease inhibitor antiretrovirals has not been studied thoroughly, we investigated whether important non-nucleoside reverse transcriptase inhibitors (NNRTI) (delavirdine, efavirenz, and nevirapine), nucleoside reverse transcriptase inhibitors (NRTI) (abacavir, emtricitabine, and lamivudine), and tenofovir as a nonnucleotide reverse transcriptase inhibitor can interact with MRP1, MRP2, and MRP3 in vitro. Inhibition of these ABC transporters was quantified by confocal laser-scanning microscopy using the 5-chloromethylfluorescein diacetate assay. With the exception of abacavir, which had no effect on MRP3, all the test compounds increased intracellular 5-chloromethylfluorescein fluorescence in a concentration-dependent manner, and this effect was observed in all the overexpressing cell lines but not in the parental cell line, indicating inhibition of MRP1, MRP2, and MRP3. In conclusion, the present study provides the first evidence for a significant and concentration-dependent inhibition of MRPs by NNRTI, NRTI, and tenofovir, which was most pronounced for delavirdine, efavirenz, and emtricitabine, suggesting that this might contribute to some of the known drug interactions impairing HIV therapy and also to the superior effectiveness of combination pharmacotherapy.
...
PMID:Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors. 1717 11

Human immunodeficiency virus 1 (HIV-1) infections are treated with HIV-protease inhibitors (PIs), nucleoside (NRTIs), non-nucleoside (NNRTIs), and nucleotide reverse transcriptase inhibitors (NtRTIs). The combined administration of antiretrovirals improves patient outcomes while increasing the likelihood of drug interactions. Indeed, as substrates, inhibitors, and occasionally also inducers of P-glycoprotein (P-gp) PIs may substantially alter the pharmacokinetics of co-administered drugs. However, the P-gp inhibitory potencies specified in the numerous publications are not comparable, because they were determined with different assays and cell lines. Moreover, data on the interaction of other anti-HIV drugs with P-gp are sparse and conflicting. We therefore aimed to clarify, which anti-HIV drugs inhibit P-gp and to compare the inhibitory potencies using two independent standard methods (calcein uptake assay, flow cytometric rhodamine123 efflux assay). In the calcein assay, all PIs, all NNRTIs, abacavir, and tenofovir disoproxil fumarate acted as P-gp inhibitors with largely differing potencies between compounds. In P388/dx cells the ranking order of inhibition was: nelfinavir>ritonavir>tipranavir>lopinavir>quinidine (positive control)>delavirdine>saquinavir>amprenavir>atazanavir>efavirenz>nevirapine>abacavir>tenofovir disoproxil fumarate. In conclusion this is the first study to provide comprehensive information on the P-gp interaction profile of anti-HIV drugs under identical assay conditions. Our study reveals that many compounds may indeed inhibit P-gp substantially and further indicates that of the various systems tested, the calcein assay in P388/dx/P388 cells is the most suitable and reliable in vitro model for the quantification of P-gp inhibition.
...
PMID:Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein. 1732 66

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.
...
PMID:Expression of cytochromes P450 3A and P-glycoprotein in human large intestine in paired tumour and normal samples. 1737 28


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---