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)

More than a decade has passed since it was unintentionally discovered that grapefruit juice interacts with certain drugs. The coadministration of these drugs with grapefruit juice can markedly elevate drug bioavailability, and can alter pharmacokinetic and pharmacodynamic parameters of the drug. The predominant mechanism for this interaction is the inhibition of cytochrome P-450 3A4 in the small intestine, resulting in a significant reduction of drug presystemic metabolism. An additional mechanism is the inhibition of P-glycoprotein, a transporter that carries drug from the enterocyte back to the gut lumen, resulting in a further increase in the fraction of drug absorbed. Some calcium channel antagonists, benzodiazepines, HMG-CoA reductase inhibitors and cyclosporine are the most affected drugs. A single exposure to one glass of the grapefruit juice can usually produce the maximal magnitude of the interaction. The data available so far, concerning this interaction and its clinical implications, are reviewed in this article. It is likely that more information regarding this interaction will accumulate in the future, and awareness of such is necessary for achieving optimal drug therapy.
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PMID:[Grapefruit juice: potential drug interaction]. 1604 29

The aim of this study was to investigate the effect of morin on the bioavailability of nimodipine after administering nimodipine (15 mg/kg) orally to rabbits either co-administered or pretreated with morin (2, 10 and 20 mg/kg). The plasma concentrations of nimodipine in the rabbits pretreated with morin were increased significantly (p < 0.05 at 10 mg/kg, p < 0.01 at 20 mg/kg) compared with the control, but the plasma concentrations of nimodipine co-administered with morin were not significant. The areas under the plasma concentration-time curve (AUC) and the peak concentrations (Cmax) of the nimodipine in the rabbits pretreated with morin were significantly higher (p < 0.05 at 10 mg/kg, p < 0.01 at 20 mg/kg), but only the Cmax of nimodipine coadministered with morin 10 mg/kg was increased significantly (p < 0.05). The absolute bioavailability (A.B%) of nimodipine in the rabbits pretreated with morin was significantly (p < 0.05 at 10 mg/kg, p < 0.01 at 20 mg/kg) higher (54.1-65.0%) than the control (36.7%). The increased bioavailability of nimodipine in the rabbits pretreated with morin might have been resulted from the morin, which inhibits the effiux pump P-glycoprotein and the first-pass metabolizing enzyme by cytochrome P-450 3A4 (CYP 3A4).
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PMID:Enhanced nimodipine bioavailability after oral administration of nimodipine with morin, a flavonoid, in rabbits. 1668 Oct 41

P-glycoprotein (P-gp), the most extensively studied ATP-binding transporter, functions as a biological barrier by extruding toxic substances and xenobiotics out of the cell. This study was carried out to determine the effect of N,N-diethyl-m-toluamide (DEET) and pyridostigmine bromide (PB), alone and in combination, on P-gp expression using Escherichia coli leaky mutant transformed with Mdr1 gene (pT5-7/mdr1), which codes for P-gp or lactose permease (pT5-7/lacY) as negative control. Also, daunomycin (a known P-gp sustrate) was used as a positive control and reserpine (a known P-gp inhibitor) served as a negative control. An in vitro cell-resistant assay was used to monitor the potential of test compounds to interact with P-gp. Following exposure of the cells to pyridostigmine bromide or daunomycin, P-gp conferred significant resistance against both compounds, while reserpine and DEET significantly inhibited the glycoprotein. Cells were grown in the presence of noncytotoxic concentrations of daunomycin, pyridostigmine bromide, reserpine, or DEET, and membrane fractions were examined by Western immunoblotting for expression of P-gp. Daunomycin induced P-gp expression quantitatively more than pyridostigmine bromide, while reserpine and DEET significantly inhibited P-gp expression in cells harboring mdr1. Photoaffinity labeling experiment performed with the P-gp ligand [125I]iodoarylazidoprazosin demonstrated that compounds that induced or inhibited P-gp transport activity also bound to P-gp. DEET was also found to be a potent inhibitor of P-gp-mediated ATPase activity, whereas pyridostigmine bromide increased P-gp ATPase activity. Cells expressing P-gp or lac permease were exposed to pyridostigmine bromide and DEET, alone and in combination. Noncytotoxic concentrations of DEET significantly inhibited P-gp-mediated resistance against pyridostigmine bromide, resulting in a reduction of the number of effective drug interactions with biological targets. An explanation of these results might be that DEET is a third-generation inhibitor of P-gp; it has high potency and specificity for P-gp, it inhibits hydrolysis of ATP, it exerts no appreciable impact on cytochrome P-450 3A4, and it prevents transport of xenobiotics, such as pyridostigmine bromide, out of the cell. This conclusion explains, at least in part, the increased toxicity and bioavailability of pyridostigmine bromide following combined administration with DEET. This study improves our understanding of the basis of chemical interactions with DEET by defining the ability of drugs to interact with P-gp either as inhibitors or substrates, which may in turn lead to altered efficacy or toxicity.
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PMID:Interaction of pyridostigmine bromide and N,N-diethyl-m-toluamide alone and in combination with P-glycoprotein expressed in Escherichia coli leaky mutant. 1672 71

Biochanin A (BCA), a phytoestrogen present in plant food and herbal products, has been reported to have cancer-preventive effects that may be mediated, in part, through effects on carcinogen metabolism. Our objective was to examine the effect of BCA on gene expression for drug-metabolizing enzymes and transporters in human hepatocytes. Cells were exposed to 20 muM of BCA for 5 days. Gene expression was assessed by a 96-gene human drug metabolism enzyme microarray. There were seven genes that were significantly up-regulated, namely cytochrome P-450 (CYP) 2A6, CYP2B6, CYP2C9, CYP2F1, multidrug resistance gene (MDR1), thromboxane A synthase 1 (TBXAS1), and SULT1A2 (sulfotransferase). Up-regulation of MDR1, which encodes for P-glycoprotein, was confirmed using real-time RT-PCR and Western analysis in hepatocytes as well as in human colon adenocarcinoma cell line (LS-180) and the induction was dose-dependent. BCA treatment up-regulated genes mainly in the CYP2 family. This induction can influence the metabolism of xenobiotics, producing effects of pharmacological and toxicological importance.
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PMID:Effects of the flavonoid biochanin A on gene expression in primary human hepatocytes and human intestinal cells. 1734 May 76

The placental trophoblast at different stages of pregnancy contains some drug transporters and xenobiotic-metabolising enzymes, as well as ligand-activated nuclear receptors, which control their inducible transcriptional regulation. Glucocorticoid receptor alpha (GRalpha) is expressed in both placental syncytiotrophoblast and cytotrophoblast. GRalpha was shown to control inducible expression of several enzymes of the cytochrome P-450 family (CYP) and the drug transporter P-glycoprotein in the liver. However, GRalpha-mediated transcriptional regulation of drug transporters and CYPs has not been studied in the placental trophoblast. In this study, we examined the expression and activity of GRalpha in the transcriptional regulation of P-glycoprotein, CYP3A4, and CYP2C9 in placental trophoblast cell lines. Employing RT-PCR, Western blotting, and luciferase gene reporter assay, we detected the expression and activity of GRalpha in JEG3 and BeWo cell lines. However, we observed that only MDR1 mRNA was up-regulated after treatment of placental cells with dexamethasone. Accordingly, only the promoter of the MDR1 gene was activated by dexamethasone in gene reporter assays in placental cells and the activation was abolished by RU486, an antagonist of GRalpha. CYP3A4 and CYP2C9 promoters were activated in placental cells only after co-transfection with hepatocyte nuclear factor 4alpha (HNF4alpha), which indicates the hepatocyte-specific character of GRalpha-mediated regulation of the genes. On the other hand, coexpression of HNF4alpha had no effect on the activation of the MDR1 gene promoter, suggesting HNF4alpha-independent regulation via GRalpha. We conclude that GRalpha may be involved in the transcriptional regulation of P-glycoprotein in the placental trophoblast. We also indicate that the CYP3A4 and CYP2C9 genes are not inducible through GRalpha in placental cell lines, due to the lack of HNF4alpha expression and possibly some additional hepatocyte-specific transcriptional factors.
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PMID:Examination of Glucocorticoid receptor alpha-mediated transcriptional regulation of P-glycoprotein, CYP3A4, and CYP2C9 genes in placental trophoblast cell lines. 1757 86

Access to antiretroviral therapy is rapidly expanding in resource-limited settings, where tuberculosis is the most common opportunistic infection. Coadministration of antitubercular and antiretroviral agents is, therefore, occurring commonly, and it is associated with 3 major complications. First, induction of cytochrome P-450 enzymes and P-glycoprotein by rifampin results in reduced concentrations of nonnucleoside reverse-transcriptase inhibitors and, particularly, protease inhibitors. This potentially results in the loss of antiviral efficacy and the development of viral resistance. Replacing rifampin with rifabutin, which does not significantly affect the concentrations of antiretroviral agents, is advocated but is currently unaffordable in resource-limited settings. Second, overlapping toxicities of antitubercular and antiretroviral agents occur frequently, necessitating discontinuation of therapy and increasing the risk of nonadherence. Third, immunopathological reactions, termed "the immune reconstitution inflammatory syndrome," occur frequently when antiretroviral therapy is initiated in patients with tuberculosis. These complexities of coadministration of antitubercular and antiretroviral agents are reviewed, and research priorities are highlighted.
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PMID:Complications of antiretroviral therapy in patients with tuberculosis: drug interactions, toxicity, and immune reconstitution inflammatory syndrome. 1762 28

HM-30181, 4-oxo-4H-chromene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxy-phenyl]-amide, is a new P-glycoprotein inhibitor with the potential to increase the cytotoxic activity of orally coadministered paclitaxel. This study was performed to characterize human cytochrome P-450 (CYP) enzymes involved in the metabolism of HM-30181 to 4- or 5-O-desmethyl-HM-30181 (M2) and 6- or 7-O-desmethyl-HM-30181 (M3) and to investigate the inhibitory potential of HM-30181 on CYP enzymes in human liver microsomes. CYP3A4 was identified as the major isozyme responsible for the O-demethylation of HM-30181 to M2 and M3 based on the correlation analysis, chemical inhibition and immuno-inhibition study and metabolism in cDNA-expressed human CYP isozymes. HM-30181 itself had no inhibitory effects on CYPs 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, and 3A4 in human liver microsomes, suggesting the possibility that the pharmacokinetics of HM-30181 could be changed with coadministration of known CYP3A4 inducers or inhibitors.
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PMID:Characterization of human liver cytochrome P-450 enzymes involved in the O-demethylation of a new P-glycoprotein inhibitor HM-30181. 1765 55

Rifampin is a potent inducer of cytochrome P-450 oxidative enzymes as well as the P-glycoprotein transport system. Several examples of well-documented clinically significant interactions include warfarin, oral contraceptives, cyclosporine, itraconazole, digoxin, verapamil, nifedipine, simvastatin, midazolam, and human immunodeficiency virus-related protease inhibitors. Rifabutin reduces serum concentrations of antiretroviral agents, but less so than rifampin. Examples of clinically relevant interactions demonstrated by recent reports include everolimus, atorvastatin, rosiglitazone/pioglitazone, celecoxib, clarithromycin, caspofungin, and lorazepam. To avoid a decreased therapeutic response, therapeutic failure, or toxic reactions when rifampin is added to or discontinued from medication regimens, clinicians need to be cognizant of these interactions. Studies and cases of rifampin drug interactions continue to increase rapidly. This review is a timely reminder to clinicians to be vigilant.
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PMID:Update on rifampin and rifabutin drug interactions. 1827 21

Herbal supplements can affect concentrations of therapeutic drugs measured in biological fluids by different mechanisms. Herbal products can either directly interfere with the methodology used in the measurement of drugs or indirectly interfere by altering the pharmacokinetics of coadministered drugs. The active components of Chan Su, Lu-Shen-Wan, Dan Shen, Asian and Siberian ginseng, oleander containing supplements, and Ashwagandha interfere with digoxin measurements by immunoassays, especially the polyclonal antibody-based immunoassays. Herbal supplements are sometimes contaminated with Western drugs causing drug toxicity. A therapeutic drug monitoring (TDM) service is very helpful for diagnosis of drug toxicity in such patients. Herbal products such as St. John's wort, a popular herbal antidepressant, increase the clearance of certain drugs either by increasing the activity of liver or intestinal cytochrome P-450 mixed-function oxidase or through modulation of the P-glycoprotein efflux pump. Significantly reduced concentrations of various therapeutic drugs such as digoxin, theophylline, cyclosporine, tacrolimus, tricyclic antidepressants, warfarin, and protease inhibitors can be observed due to interaction of these drugs with St. John's wort, causing treatment failure. On the other hand, a few drugs such as carbamazepine, mycophenolic acid, and procainamide do not show any interaction with St. John's wort. Understanding the effect of herbal products on TDM methodologies and identification of interactions between herbal products and drugs by TDM are very important clinically.
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PMID:Herbal supplements and therapeutic drug monitoring: focus on digoxin immunoassays and interactions with St. John's wort. 1836 83

Synthetic food dyes are xenobiotics, and, after ingestion, portions of these dyes may be absorbed and metabolized by phase I and II drug-metabolizing enzymes, and excreted by transporters of phase III enzymes. In the previous report, it was shown that inhibition of UDP-glucuronosyltrasnferase 1A6 occurred following ingestion of phloxine, erythrosine, and rose bengal present in 12 permitted synthetic food dyes. In this report, the influence of dyes was examined on CYP3A4, a major phase I drug-metabolizing enzyme, and P-glycoprotein, a major transporter by synthetic food dyes. Human cytochrome P-450 (CYP) 3A4 and P-glycoprotein were inhibited by xanthene food dyes. The IC(50) values of these dyes to inhibit CYP3A4 and P-glycoprotein were the same as the level of inhibition of UGT1A6 produced by three haloganated xanthene food dyes in the previous report, except acid red, which inhibited only CYP3A4. Data suggest that inhibition by dyes is not enzyme specific but may be in a membrane-specific or protein-specific manner, such as conformational changes in protein. In the previous study, it was suggested that inhibition by dyes depended upon light irradiation due to generation of (1)O2 from these dyes. In this study, the influence of superoxide dismutase and catalase on inhibition by dyes was examined. Superoxide dismutase but not catalase was effective in preventing the inhibition of UGT1A6 by the dyes. Data suggest that superoxide anions, originating from dyes via light irradiation, may attack drug-metabolizing enzymes. It is possible that red cosmetics containing phloxine, erythrosine, or rose bengal react with proteins in skin and may lead to skin damage.
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PMID:Inhibition of human CYP3A4, UGT1A6, and P-glycoprotein with halogenated xanthene food dyes and prevention by superoxide dismutase. 1868 1


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