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)

AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in human immunodeficiency virus-infected patients. Since AMD070 is a substrate of cytochrome P450 3A4 and P-glycoprotein, both of which may be affected by ritonavir, we tested for a ritonavir effect on AMD070 pharmacokinetics. Subjects were given a single 200-mg dose of AMD070 on days 1, 3, and 17. Ritonavir (100 mg every 12 h) was dosed from day 3 to day 18. Blood samples to test for AMD070 concentrations were collected over 48 h after each administration of AMD070. Twenty-three male subjects were recruited. Among them, 21 completed the study, and 2 were discontinued for reasons other than safety. All adverse events were grade 2 or lower. AMD070 alone had the following pharmacokinetic features, given as medians (ranges): 3 h (0.5 to 4 h) for the time to peak blood concentration, 256 ng/ml (41 to 845 ng/ml) for the peak concentration (C(max)), 934 h x ng/ml (313 to 2,127 h x ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), 214 liters/h (94 to 639 liters/h) for apparent body clearance, and 4,201 liters (1,996 to 9,991 liters) for the apparent volume of distribution based on the terminal phase. The initial doses of ritonavir increased the C(max) of AMD070 [geometric mean (90% confidence interval)] by 39% (3 to 89%) and the AUC(0-infinity) by 60% (29 to 100%). After 14 days of ritonavir dosing, the pharmacokinetic changes in AMD070 persisted. The plasma pharmacokinetics of ritonavir were consistent with previous reports. It is concluded that AMD070 concentrations were increased with concomitant ritonavir dosing for 14 days in healthy volunteers.
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PMID:Effect of low-dose ritonavir on the pharmacokinetics of the CXCR4 antagonist AMD070 in healthy volunteers. 1828 77

Many anti-human immunodeficiency virus 1 nucleoside reverse-transcriptase inhibitors have low central nervous system (CNS) distribution due in part to active efflux transport at the blood-brain barrier. We have previously shown that zidovudine (AZT) and abacavir (ABC) are in vitro substrates for the efflux transport protein breast cancer resistance protein (Bcrp) 1. We evaluated the influence of Bcrp1 on plasma pharmacokinetics and brain penetration of zidovudine and abacavir in wild-type and Bcrp1-deficient (Bcrp1-/-) FVB mice. There was no difference in either area under the concentration-time profiles for plasma (AUC(plasma)) or brain (AUC(brain)) for zidovudine between the wild-type and Bcrp1-/- mice. The AUC(plasma) of abacavir was 20% lower in the Bcrp1-/- mice, whereas the AUC(brain) was 20% greater. This difference resulted in a 1.5-fold increase in abacavir brain exposure in the Bcrp1-/- mice. The effect of selective and nonselective transport inhibitors on the ABC brain/plasma ratio at a single time point was evaluated. 3-(6-Isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6, 7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-3-yl)-propionicacid tert-butyl ester (Ko143), N[4[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide (GF120918), probenecid, and Pluronic P85 increased abacavir plasma concentrations in the wild-type mice. Abacavir plasma concentrations in Bcrp1-/- mice were increased by (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo (a,e)cyclopropa(c)cycloheptan-6-yl)-alpha-((5-quinoloyloxy)methyl)-1-piperazineethanol trihydrochloride (LY335979), GF120918, and probenecid, but not by Ko143. Brain/plasma concentration ratios in both the wild-type and Bcrp1-/- mice were increased by the P-glycoprotein inhibitors LY335979 and GF120918, but not by BCRP-selective inhibitors. These data indicate that deletion of Bcrp1 has little influence on the pharmacokinetics or brain penetration of AZT. However, for abacavir, deletion of Bcrp1 reduces plasma exposure and enhances brain penetration. These findings suggest that Bcrp1 does not play a significant role in limiting the CNS distribution of zidovudine and abacavir; however, brain penetration of abacavir is dependent on P-glycoprotein-mediated efflux.
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PMID:Investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) on pharmacokinetics and central nervous system penetration of abacavir and zidovudine in the mouse. 1844 33

The plasma concentrations of orally administered anti-human immunodeficiency virus protease inhibitors are significantly reduced during human and mouse pregnancy. We have shown that in the mouse, at gestational day 19, this reduction is due to increased hepatic cytochrome P450 3a (Cyp3a) protein expression and activity. In the current study, we investigated the mechanisms by which Cyp3a activity is increased by pregnancy and the time course of change in expression of Cyp3a and P-glycoprotein (P-gp) in various tissues. We found that hepatic transcripts of Cyp3a16, Cyp3a41, and Cyp3a44 were significantly increased during pregnancy, whereas those of Cyp3a11 and Cyp3a25 were significantly decreased. This resulted in a net increase in Cyp3a protein expression and activity in the liver during pregnancy. The increase in Cyp3a41 and Cyp3a44 transcripts was positively correlated (p < 0.05) with hepatocyte nuclear factor 6 and estrogen receptor-alpha transcripts. The pregnancy-related factors that transcriptionally activated mouse Cyp3a isoforms also activated the human CYP3A4 promoter in pregnant CYP3A4-promoter-luciferase transgenic (CYP3A4-tg) mice. In contrast, intestinal Cyp3a protein expression was not significantly affected by pregnancy. No change in P-gp protein expression was observed in the liver or kidney during pregnancy, although a significant decrease was observed in the placenta. Because hepatic CYP3A activity also seems to be induced during human pregnancy, the mouse (including CYP3A4-tg mouse) seems to be an excellent animal model to determine the molecular mechanisms for such an induction.
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PMID:Effect of pregnancy on cytochrome P450 3a and P-glycoprotein expression and activity in the mouse: mechanisms, tissue specificity, and time course. 1850 67

Human immunodeficiency virus (HIV)-1 patients who abuse opiates are at a greater risk of developing neurological complications of AIDS. Alterations in blood-brain barrier (BBB) integrity are associated with cytoskeletal disorganization and disruption of tight junction (TJ) integrity. We hypothesize that opiates in combination with HIV-1 viral proteins can modulate TJ expression in primary brain microvascular endothelial cells (BMVEC), thereby compromising BBB integrity and exacerbating HIV-1 neuropathogenesis. We investigated the effect of morphine and/or tat on the expression of TJ proteins ZO-1, JAM-2, Occludin and P-glycoprotein and the functional effects of TJ modulation in BMVEC. Morphine and/or tat, via the activation of pro-inflammatory cytokines, intracellular Ca(2+) release, and activation of myosin light chain kinase, modulated TJ expression resulting in decreased transendothelial electric resistance and enhanced transendothelial migration across the BBB. These studies may lead to the development of novel anti-HIV-1 therapeutics that target specific TJ proteins, thus preventing TJ disruption in opiate using HIV-1 patients.
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PMID:Tight junction regulation by morphine and HIV-1 tat modulates blood-brain barrier permeability. 1857 77

Limited drug penetration is an obstacle that is often encountered in the treatment of CNS diseases including human immunodeficiency virus type-1 (HIV-1) encephalitis (HIVE). One mechanism that may contribute to this phenomenon is the expression of ATP-binding cassette (ABC) drug efflux transporters [i.e., P-glycoprotein (P-gp), Multidrug Resistance-Associated Proteins (MRP/Mrp), Breast Cancer Resistance Protein (BCRP; also known as ABCG2)] at the primary brain barrier sites (i.e., blood-brain barrier, blood-cerebrospinal fluid barrier). In addition, it has been recently proposed that glial cells may also contribute to the low accumulation and altered distribution of therapeutic compounds in the CNS by functioning as a "secondary barrier." In fact, a few studies have shown that ABC transporters are both expressed and functional in glial cells. Furthermore, commonly prescribed antiretroviral compounds (ARVs), particularly HIV-1 protease inhibitors, are substrates for many of these same transport proteins suggesting that ABC transporters in glial cells may contribute to the overall export of these drugs from the brain. HIV-1 infection is a chronic condition characterized by long-term exposure of brain cellular compartments to HIV-1 virions and soluble viral proteins. In addition, treatment of HIV-1 infection involves long-term administration of a multiplicity of ARVs (i.e., HAART regimens). Indeed, pathological factors associated with HIV-1 infection and/or pharmacological factors related to treatment may alter the expression of ABC transporters and lead to changes in CNS ARV uptake and/or distribution. This review summarizes recent knowledge in this area and emphasizes the role that glial ABC transporters may play in regulating ARV transport.
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PMID:Regulation of ABC membrane transporters in glial cells: relevance to the pharmacotherapy of brain HIV-1 infection. 1864 2

1. Growing knowledge of the pathogenesis of human immunodeficiency virus (HIV)-1 infection has led to the identification of potential virus sanctuary sites within the central nervous system and gut-associated lymphoid tissue. 2. Maraviroc is a novel CCR5 antagonist for the treatment of HIV-1 infection. Disposition studies have been performed within the preclinical testing of maraviroc to determine its distribution to these anatomical sites. 3. Maraviroc, which is a substrate of the efflux transporter P-glycoprotein, shows limited distribution to the central nervous system as evidenced by cerebrospinal fluid concentrations that were 10% of the free plasma concentration following intravenous infusion to rats. Tissue distribution studies also indicated limited distribution of radioactivity into brain tissue of rats. 4. Radioactivity in gut-associated lymphoid tissue lymph nodes exceeded the concentrations in blood and concentrations in the contents of thoracic ducts of the lymphatic system were similar to blood levels following intravenous administration to rats.
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PMID:Preclinical assessment of the distribution of maraviroc to potential human immunodeficiency virus (HIV) sanctuary sites in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT). 1885 88

A major concern regarding the chronic administration of antiretroviral drugs is the potential for induction of drug efflux transporter expression (i.e., P-glycoprotein, P-gp) at tissue sites that can significantly affect drug distribution and treatment efficacy. Previous data have shown that the inductive effect of human immunodeficiency virus protease inhibitors (PIs) is mediated through the human orphan nuclear receptor, steroid xenobiotic receptor (SXR or hPXR). The objectives of this study were to investigate transport and inductive properties on efflux drug transporters of two PIs, atazanavir and ritonavir, at the blood-brain barrier by using a human brain microvessel endothelial cell line, hCMEC/D3. Transport properties of PIs by the drug efflux transporters P-gp and multidrug resistance protein 1 (MRP1) were assessed by measuring the cellular uptake of (3)H-atazanavir or (3)H-ritonavir in P-gp and MRP1 overexpressing cells as well as hCMEC/D3. Whereas the P-gp inhibitor, PSC833, increased atazanavir and ritonavir accumulation in hCMEC/D3 cells by 2-fold, the MRP inhibitor MK571 had no effect. P-gp, MRP1, and hPXR expression and localization were examined by Western blot analysis and immunogold cytochemistry at the electron microscope level. Treatment of hCMEC/D3 cells for 72 hr with rifampin or SR12813 (two well-established hPXR ligands) or PIs (atazanavir or ritonavir) resulted in an increase in P-gp expression by 1.8-, 6-, and 2-fold, respectively, with no effect observed for MRP1 expression. In hCMEC/D3 cells, cellular accumulation of these PIs appears to be primarily limited by P-gp efflux activity. Long-term exposure of atazanavir or ritonavir to brain microvessel endothelium may result in further limitations in brain drug permeability as a result of the up-regulation of P-gp expression and function.
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PMID:Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line. 1885 43

P-glycoprotein (P-gp) is an efflux transporter that controls the intracellular concentrations of drugs. Human development may modulate P-gp function. We investigated the effect of age on P-gp activity and MDR1 gene expression in lymphocytes. We also assessed the influence of human immunodeficiency virus (HIV) infection. We used 3,3'-diethyloxacarbocyanin iodide (DiOC(6)) efflux, estimated by flow cytometry, to quantify P-gp activity in 94 children (age range, 0-18 years) and 25 adults. MDR1 gene expression was quantified using reverse transcription-PCR (RT-PCR). In T and natural killer (NK) cell populations, P-gp activity peaked at birth, decreased between the ages of 0 and 6 months, and stabilized between the ages of 6 months and 2 years (P < 10(-6)). These maturation profiles were also strongly correlated (r = 0.67, P < 10(-6)). HIV infection did not affect P-gp activity in the lymphocytes of children. MDR1 gene expression was not influenced by age, nor was it correlated with P-gp activity. The high levels of P-gp activity observed in the lymphocytes of children ~6 months of age may affect the efficacy of intracellular drugs.
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PMID:High levels of P-glycoprotein activity in human lymphocytes in the first 6 months of life. 1903 99

Efflux proteins have been shown to greatly affect the uptake of antiretroviral drugs by cells and to hamper their access to the human immunodeficiency virus type 1 replication site. This study evaluated the factors that may lead to drug-drug interactions between emtricitabine (FTC), tenofovir (TFV), and efavirenz (EFV), including the modulation of efflux transporter expression and function. Peripheral blood mononuclear cells from healthy volunteers were used to determine whether or not an interaction between antiretroviral drugs and target cells occurred in any combination of FTC, TFV, EFV, FTC-TFV, TFV-EFV, or FTC-TFV-EFV. Following 20 h of treatment, intracellular drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Efflux transporter functionality and inhibitor drug properties were assessed by measuring fluorescent dye efflux. ABCB1 (P-glycoprotein), ABCC 1 to 6 (multidrug resistance-associated protein), and OAT (organic anion transporter) expression in response to the treatments was quantified by semiquantitative real-time PCR. Cells treated with a double combination (FTC-TFV or TFV-EFV) or the triple combination (FTC-TFV-EFV) produced higher FTC and TFV intracellular concentrations than cells treated with FTC or TFV alone. However, no change in the EFV intracellular concentration was observed. FTC tended to induce abcc5 mRNA expression and EFV tended to induce abcc1 and abcc6 mRNA expression, whereas TFV tended to reduce mdr1, abcc1, abcc5, and abcc6 mRNA expression. Under these conditions, a decrease in the functionality of ABCC was observed, and this decrease was associated with the direct inhibitory actions of these drugs. This in vitro study reveals a benefit of the combination FTC-TFV-EFV in terms of the intracellular FTC and TFV concentrations and highlights the pharmacological mechanisms that lead to this effect.
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PMID:Combination of tenofovir and emtricitabine plus efavirenz: in vitro modulation of ABC transporter and intracellular drug accumulation. 1907 72

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined ritonavir effects on stereoselective methadone pharmacokinetics and clinical effects (pupillary miosis) in healthy human immunodeficiency virus-negative volunteers. Subjects received intravenous plus oral (deuterium-labeled) racemic methadone after no ritonavir, short-term (3-day) ritonavir, and steady-state ritonavir. Acute and steady-state ritonavir, respectively, caused 1.5- and 2-fold induction of systemic and apparent oral R- and S-methadone clearances. Ritonavir increased renal clearance 40-50%, and stereoselectively (S > R) increased hepatic methadone N-demethylation 50-80%, extraction twofold, and clearance twofold. Bioavailability was unchanged despite significant inhibition of intestinal P-glycoprotein. Intestinal and hepatic CYP3A was inhibited > 70%. Ritonavir shifted methadone plasma concentration-miosis curves leftward and upward. Rapid ritonavir induction of methadone clearance results from increased renal clearance and induced hepatic metabolism. Induction of methadone metabolism occurred despite profound CYP3A inhibition, suggesting no role for CYP3A in clinical methadone metabolism and clearance. Ritonavir may alter methadone pharmacodynamics.
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PMID:Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: I. Evidence against CYP3A mediation of methadone clearance. 1923 55


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