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:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The protease inhibitor (PI) indinavir may be used in the management of human immunodeficiency virus (HIV) infection during pregnancy. Poor maternal-to-fetal transfer of indinavir has been reported previously, but the mechanisms of transfer remain unknown. The bidirectional transfer of indinavir was assessed in dually perfused, isolated human placentae. Term placentae (n = 5) were obtained from non-HIV-infected pregnant women. To investigate transport mechanisms, the steady-state transfer of indinavir was compared to those of antipyrine (a marker of passive diffusion) and [(3)H]vinblastine (a marker of P-glycoprotein [P-gp] transport) in the maternal-to-fetal and fetal-to-maternal directions in each placenta. Indinavir and antipyrine perfusate concentrations were determined by using reverse-phase, high-performance liquid chromatography; [(3)H]vinblastine concentrations were measured by liquid scintillation. The antipyrine transfer clearance in each direction did not differ (P = 0.76), a finding consistent with passive diffusion. However, the maternal-to-fetal transfer clearance of vinblastine, normalized to that of antipyrine (clearance index) (0.31 +/- 0.05), was significantly lower than the fetal-to-maternal clearance index of vinblastine (0.67 +/- 0.17; P = 0.017), suggesting the involvement of placental P-gp. Similarly, the maternal-to-fetal clearance index of indinavir (0.39 +/- 0.09) was significantly lower than its fetal-to-maternal clearance index (0.97 +/- 0.12; P < 0.001). These results represent the first evidence for differential transfer of a xenobiotic in the intact human placenta. The use of transport modulators to increase the maternal-to-fetal transfer of PIs as a possible strategy to reduce mother-to-child transmission of HIV warrants investigation.
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PMID:Differential bidirectional transfer of indinavir in the isolated perfused human placenta. 1572 98

P-glycoprotein (P-gp) is an efflux pump responsible for limiting oral bioavailability, tissue penetration and increasing metabolism of the HIV protease inhibitor saquinavir (SQV). The objective of this study is to investigate whether prodrug derivatization of SQV to novel dipeptide prodrugs Val-Val-saquinavir (Val-Val-SQV) and Gly-Val-saquinavir (Gly-Val-SQV) targeting peptide transporters can enhance cellular permeability of saquinavir and modulate P-gp mediated efflux. Uptake and transport studies were conducted employing MDCKII-MDRI cell line at 37 degrees C for 10 min and 3 h, respectively. Uptake of [3H]ritonavir and [3H]erythromycin, utilized as model P-gp substrates, was carried out in the presence of inhibitory concentration of SQV and its peptide prodrugs. Bidirectional transport studies were conducted on MDCKII-MDR1 cells grown over membrane inserts. Uptake of [3H]erythromycin by MDCKII-MDR1 cells exhibited a four-fold increase in the presence of 75 microM SQV. However, equimolar concentrations of Val-Val-SQV and Gly-Val-SQV showed only 2.5-fold increase in [3H]erythromycin uptake. Concentration dependent inhibition of [3H]glycylsarcosine (Gly-Sar), a model peptide transporter substrate, was observed in the presence of SQV prodrugs. Transepithelial transport studies of Val-Val-SQV and Gly-Val-SQV exhibited an enhanced absorptive flux and reduced secretory flux relative to studies employing SQV. These results are very likely due to decreased efflux of SQV dipeptide prodrugs by P-gp. Peptide prodrug derivatization constitutes an exciting strategy to improve intestinal absorption and oral bioavailability of SQV.
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PMID:Evasion of P-gp mediated cellular efflux and permeability enhancement of HIV-protease inhibitor saquinavir by prodrug modification. 1613 47

Multidrug resistance-associated protein (Mrp) 2-deficient transport-deficient (TR(-)) rats, together with their transport-competent Wistar counterparts (wild type), have been used to examine the contribution of Mrp2 to drug disposition. However, little is known about potential variation in expression of other transport proteins between TR(-) and wild-type rats or whether these differences are tissue-specific. Sections of liver, kidney, brain, duodenum, jejunum, ileum, and colon were obtained from male TR(-) and wild-type Wistar rats. Samples were homogenized in protease inhibitor cocktail and ultracentrifuged at 100,000g for 30 min to obtain membrane fractions. Mrp2, Mrp3, Mrp4, P-glycoprotein, sodium-dependent taurocholate cotransporting polypeptide, organic anion transporting polypeptides 1a1 and 1a4, bile salt export pump, breast cancer resistance protein, ileal bile acid transporter, UDP-glucuronosyl transferase (UGT1a), glyceraldehyde-3-phosphate dehydrogenase, and beta-actin protein expression were determined by Western blot. Mrp3 was significantly up-regulated in the liver ( approximately 6-fold) and kidney ( approximately 3.5-fold) of TR(-) rats compared with wild-type controls. Likewise, the expression of UGT1a enzymes was increased in the liver and kidney of TR(-) rats by approximately 3.5- and approximately 5.5-fold, respectively. Interestingly, Mrp3 expression was down-regulated in the small intestine of TR(-) rats, but expression was similar to wild type in the colon. Mrp4 was expressed to varying extents along the intestine. Expression of some transport proteins and UGT1a enzymes differ significantly between TR(-) and wild-type rats. Therefore, altered drug disposition in TR(-) rats must be interpreted cautiously because up- or down-regulation of other transport proteins may play compensatory roles in the presence of Mrp2 deficiency.
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PMID:Characterization of transport protein expression in multidrug resistance-associated protein (Mrp) 2-deficient rats. 1620 65

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.
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PMID:Dependence of nelfinavir brain uptake on dose and tissue concentrations of the selective P-glycoprotein inhibitor zosuquidar in rats. 1643 46

Concurrent use of natural health products (NHPs) with antiretroviral drugs (ARVs) is widespread among human immunodeficiency virus-infected patients. This article reviews the clinical pharmacokinetic and pharmacodynamic interactions between NHPs and ARVs. Many NHPs are complex mixtures and are likely to contain organic compounds that may induce and/or inhibit drug metabolizing enzymes and drug transporters. Although the weight of evidence for the effects of certain NHPs varies and many studies of these products lack scientific rigor, it has been observed that St. John's wort clearly induces cytochrome P450 3A4 and P-glycoprotein and reduces protease inhibitor and nonnucleoside reverse-transcriptase inhibitor concentrations, thereby increasing the likelihood of therapeutic failure. Limited clinical research suggests that intake of garlic and vitamin C results in reductions in ARV concentrations. The intake of milk thistle, Echinacea species, and goldenseal inhibits cytochrome P450 enzymes in vitro and may increase ARV concentrations, but by clinically unimportant amounts. Intake of fish oil reduces ARV-induced hypertriglyceridemia without significantly affecting lopinavir concentrations. Before recommending the use of NHPs as adjuncts to ARV use, studies should first exclude significant pharmacokinetic interactions and ensure that ARV efficacy is maintained.
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PMID:Interactions between natural health products and antiretroviral drugs: pharmacokinetic and pharmacodynamic effects. 1698 20

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.
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PMID:Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors. 1717 11

Saquinavir (SQV) was the first human immuno-virus-1 (HIV-1) protease inhibitor approved by FDA. However, P-glycoprotein (P-gp), an efflux pump limits its oral and brain bioavailabilities. The objective of this study is to investigate whether prodrug modification of SQV to dipeptide prodrugs Valine-Valine-Saquinavir (Val-Val-SQV) and Glycine-Valine-Saquinavir (Gly-Val-SQV) targeting intestinal peptide transporter can enhance intestinal permeability of SQV by circumventing P-gp mediated efflux. Single pass intestinal perfusion experiments in rat jejunum were performed to calculate the absorption rate constant and intestinal permeability of SQV, Val-Val-SQV and Gly-Val-SQV. Equimolar concentration (25 microM) of SQV, Val-Val-SQV and Gly-Val-SQV were employed in the perfusion studies. Perfusion experiments were also carried out in the presence of cyclosporine (10 microM) and glycyl-sarcosine (20 mM). Absorption rate constants in rat jejunum (ka) for SQV, Val-Val-SQV and Gly-Val-SQV were found to be 14.1+/-3.4x10(-3), 65.8+/-4.3x10(-3), and 25.6+/-5.7x10(-3) min(-1), respectively. Enhanced absorption of Val-Val-SQV and Gly-Val-SQV relative to SQV can be attributed to their translocation by the peptide transporter in the jejunum. Significant permeability enhancement of SQV across rat jejunum was observed in the presence of cyclosporine 10 microM (P-gp inhibitor). However, permeability of Val-Val-SQV was unchanged in the presence of cyclosporine suggesting lack of any interaction of the prodrug with efflux pump. Intestinal absorption of Val-Val-SQV was significantly inhibited in the presence of gly-sar indicating the involvement of peptide transporter in intestinal absorption. In conclusion, peptide transporter targeted prodrug modification of P-gp substrates could lead to shielding of these drug molecules from efflux pumps.
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PMID:Intestinal absorption of novel-dipeptide prodrugs of saquinavir in rats. 1720 46

P-glycoprotein (P-gp) can compromise the antiretroviral effect of a protease inhibitor (PI)-containing regimen for HIV-1, but can also reduce HIV-1 replication. We studied the net effect of P-gp on the intracellular HIV-1 RNA and DNA load in vivo. CD4(+) T cells were isolated from 27 HIV-1 patients (13 without and 14 with a PI-containing regimen) and subsequently sorted in CD45RO(-) (naive) and CD45RO(+) (memory) subsets with either high (P-gp(high)) or low (P-gp(low)) P-gp activity. Unspliced HIV-1 RNA and HIV-1 DNA load were determined. For each patient P-gp(high) and P-gp(low) subsets were compared. In patients on a PI-containing regimen, intracellular unspliced HIV-1 RNA was significantly lower in P-gp(high)-naive CD4(+) cells compared to P-gp(low)-naive CD4(+) cells (p = 0.04). The same trend was seen in naive CD4(+) cells of treatment naive patients. In both treated and untreated patients HIV-1 DNA levels were significantly lower in P-gp(high) than in P-gp(low) memory CD4(+) cells (p = 0.02 and p = 0.04). High cellular P-gp activity coincided with a reduced intracellular HIV-1 load in vivo, both in therapy-naive and in PI-treated patients. Therefore we conclude that the potential efflux function of P-gp on PIs may be clinically less relevant than the effect of P-gp on intracellular HIV-1 replication.
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PMID:Antiviral activity of HIV type 1 protease inhibitors nelfinavir and indinavir in vivo is not influenced by P-glycoprotein activity on CD4+ T cells. 1726 28

Tipranavir is a nonpeptidic protease inhibitor that has activity against human immunodeficiency virus strains resistant to multiple protease inhibitors. Tipranavir 500 mg is coadministered with ritonavir 200 mg. Tipranavir is metabolized by cytochrome P450 (CYP) 3A and, when combined with ritonavir in vitro, causes inhibition of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in addition to induction of glucuronidase and the drug transporter P-glycoprotein. As a result, drug-drug interactions between tipranavir-ritonavir and other coadministered drugs are a concern. In addition to interactions with other antiretrovirals, tipranavir-ritonavir interactions with antifungals, antimycobacterials, oral contraceptives, statins, and antidiarrheals have been specifically evaluated. For other drugs such as antiarrhythmics, antihistamines, ergot derivatives, selective serotonin receptor agonists (or triptans), gastrointestinal motility agents, erectile dysfunction agents, and calcium channel blockers, interactions can be predicted based on studies with other ritonavir-boosted protease inhibitors and what is known about tipranavir-ritonavir CYP and P-glycoprotein utilization. The highly complex nature of drug interactions dictates that cautious prescribing should occur with narrow-therapeutic-index drugs that have not been specifically studied. Thus, the known interaction potential of tipranavir-ritonavir is reported, and in vitro and in vivo data are provided to assist clinicians in predicting interactions not yet studied. As more clinical interaction data are generated, better insight will be gained into the specific mechanisms of interactions with tipranavir-ritonavir.
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PMID:Mechanisms of pharmacokinetic and pharmacodynamic drug interactions associated with ritonavir-enhanced tipranavir. 1754 71

Extended treatment with human immunodeficiency virus (HIV) protease inhibitors (HPIs) is standard in HIV/AIDS therapy. While these drugs have helped decrease the overall incidence of AIDS defining illnesses, the relative prevalence of HIV/AIDS dementia has increased. HPIs may cause induction of blood-brain barrier (BBB) drug transporters (P-glycoprotein; P-gp) and thereby limit entry of HPIs into brain tissue, increasing the probability that the brain could become an HIV sanctuary site. Using bovine brain microvessel endothelial cells (BMEC) as an in-vitro model of the BBB, the potential for the HIV protease inhibitor ritonavir to cause induction of P-gp activity and expression was examined. BMEC were isolated from fresh cow brain by enzymatic digest and density centrifugation. Primary culture BMEC were co-incubated with ritonavir or vehicle control for 120 h. Quantitative drug accumulation of rhodamine 123 (Rh123) and fluorescence microscopy were used as measures of P-gp activity. P-gp expression was assessed using quantitative Western blotting. Ritonavir decreased Rh123 cell accumulation and increased P-gp immunoreactive protein in a concentration-dependent manner. Fluorescent microscopy mirrored Rh123 quantitative studies. In BMEC pretreated with 30 microM ritonavir, Rh123 accumulation was decreased 40% and immunoreactive P-gp protein increased 2-fold. Collectively, a strong correlation between decreased Rh123 BMEC accumulation and increased P-gp immunoreactive protein was observed (Spearman r2 = 0.77, P < 0.0001). Thus extended exposure of BMEC to ritonavir caused a concentration-dependent increase in P-gp activity and expression. Similar findings may occur at the clinical level with prolonged HIV protease inhibitor use, giving insight into the central nervous system as an HIV sanctuary site and eventual development of HIV dementia.
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PMID:Induction of P-glycoprotein expression and activity by ritonavir in bovine brain microvessel endothelial cells. 1763 89


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