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)

Valspodar (Amdray, SDZ PSC 833) is derived from cyclosporin, but lacks the immunosuppressive and most of the collateral activities of cyclosporin A (CsA, Sandimmune, Neoral); it exhibits an enhanced capacity to chemosensitise tumour cells showing the classical type multiple drug-resistance (MDR) associated with MDR1 P-glycoprotein (Pgp) overexpression. This valspodar-mediated chemosensitisation of MDR tumour cells is reviewed with regard to its mechanism of inhibition on Pgp flippase function, and its potential inhibition of anticancer drug (ACD) metabolisation by CYP3A enzymes is discussed. Potent inhibition of the membranous and cytoplasmic detoxification mechanisms expressed by cells at the absorption and clearance borders in the body by valspodar results in the many pharmacokinetic interactions with other drugs that are substrates of either, or both, Pgp and CYP classes of detoxifying enzyme. In view of the present ability to restrict oral bioavailability of valspodar within a narrow range, and to adapt adequately the chemotherapeutic dosages to achieve their equivalent exposure in the presence or absence of valspodar, current clinical data on its efficacy and safety permit optimism for ongoing Phase III trials. The potential of valspodar to increase exposure or to modulate the biodistribution of other chemotherapeutics, such as HIV protease inhibitors to the brain, is further evoked, as this might become another application of the new drug. This evaluation of valspodar compared to CsA attempts to interpret its mechanisms of action, rather than to serve as a complete and comparative repertoire of all published preclinical and clinical data.
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PMID:Valspodar: current status and perspectives. 1599 33

The tuberculostatic compound rifampin (INN, rifampicin) induces the expression of a number of drug metabolism-related genes involved in multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), cytochromes (cytochrome P450 [CYP] 3A4), uridine diphosphate-glucuronosyltransferases, monoamine oxidases, and glutathione S -transferases. Drugs that depend on these enzymes for their metabolism are prone to drug interactions when coadministered with rifampin. A novel, clinically relevant drug interaction is described between rifampin and mycophenolate mofetil (MMF), a cornerstone immunosuppressive molecule used in solid organ transplantation. Long-term rifampin therapy caused a more than twofold reduction in dose-corrected mycophenolic acid (MPA) exposure (dose-interval area under the concentration curve from 0 to 12 hours [AUC 0-12]) when administered simultaneously in a heart-lung transplant recipient, whereas subsequent withdrawal of rifampin resulted in reversal of these changes after 2 weeks of washout (dose-corrected AUC 0-12 after rifampin withdrawal, 19.7 mg.h.L-1.g -1 versus 6.13 mg.h.L-1.g-1 before rifampin withdrawal [221% change]; dose-uncorrected AUC 0-12 after rifampin withdrawal, 29.6 mg.h/L [daily MMF dose, 3 g] versus 18.4 mg.h/L [daily MMF dose, 6 g] during rifampin administration [60.8% change]). Failure to recognize this drug interaction could potentially lead to MPA underexposure and loss of clinical efficacy. The effect of rifampin on MPA metabolism can, at least in part, be explained by simultaneous induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA.
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PMID:Drug interaction between mycophenolate mofetil and rifampin: possible induction of uridine diphosphate-glucuronosyltransferase. 1600 96

The present interest and widespread use of herbal remedies has created the possibility of interaction between them and pharmaceutical drugs if they are used simultaneously. Before the recent reports of apparent hepatotoxicity associated with its use, kava (Piper methysticum Forst. F.), was one of the top 10 selling herbal remedies in Europe and North America. This adverse effect was not previously encountered with the traditional beverage which was prepared as a water infusion in contrast to the commercial products which are extracted with organic solvents. Kavalactones, the active principles in kava, are potent inhibitors of several of the CYP 450 enzymes, suggesting a high potential for causing pharmacokinetic interactions with drugs and other herbs which are metabolized by the same CYP 450 enzymes. Furthermore, some kavalactones have been shown to possess pharmacological effects, such as blockade of GABA receptors and sodium and calcium ion channels, which may lead to pharmacodynamic interactions with other substances which possess similar pharmacological proprieties. St. John's wort (Hypericum perforatum L.), used extensively for the treatment of mild to moderate clinical depression, has long been considered safer than the conventional pharmaceutical agents. However, its ability, through its active constituents hypericin, pseudohypericin and hyperforin, to induce intestinal P-glycoprotein/MRD1 and both intestinal and hepatic CYP3A4 enzyme, could markedly reduce the distribution and disposition of their co-substrates. In addition, St. John's wort is a potent uptake inhibitor of the neurotransmitters serotonin, norepinephrine and dopamine all of which have a role in mood control. Consequently, the very real potential for a pharmacodynamic interaction between the herb and pharmaceutical drugs which share this mechanism of action and, like St. John's wort, are used for mood elevation. However, presently there is very little evidence to substantiate actual pharmacokinetic and/or pharmacodynamic interaction between drugs and kava or St. John's wort. This review provides a brief overview of the existing data on interactions of kava and St. John's wort with pharmaceutical agents and as a result reveals the urgent need for detailed investigations to identify clinically significant interactions for these herbal remedies that have the potential to cause adverse effects.
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PMID:Potential for interaction of kava and St. John's wort with drugs. 1600 88

Increased systemic exposure to statins and consequent risk for complications has been reported in patients concomitantly treated with cyclosporin A (CsA). This has been ascribed to inhibition of drug catabolism by cytochrome P450 3A4 (CYP3A4) or drug transport by P-glycoprotein (PGP) and organic anion transporting polypeptide (OATP1B1). It is not known whether the combination of statins and tacrolimus (Tac) also suffers from this drawback. Therefore, a pharmacokinetic study of atorvastatin and its metabolites was performed in 13 healthy volunteers after 4 days' treatment, and after short (12 h) concomitant exposure to CsA and Tac. A complementary assessment of overall CYP, and hepatic and intestinal CYP3A4+PGP activity was performed after each treatment episode and compared to baseline (no drugs). Systemic exposure to atorvastatin acid and its metabolites was significantly increased when administered with CsA. In contrast, intake of Tac did not have any impact on atorvastatin pharmacokinetics. Concomitantly, a profound decrease of hepatic and intestinal PGP and an increase of intestinal CYP3A4 were noted with CsA, whereas no effect was seen after atorvastatin therapy with or without Tac. Based on these findings treatment with Tac appears a safer option for patients needing a combination of statins and calcineurin inhibitors.
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PMID:Combined therapy with atorvastatin and calcineurin inhibitors: no interactions with tacrolimus. 1609 3

The use of polytherapy in clinical practice necessitates an appreciation and understanding of the potential for drug interactions. Recent publications provide insight into the role of the active transport systems P-glycoprotein (P-gp) and human organic anion-transporting polypeptides (OATPs) in drug interactions. Active drug transporters influence the bioavailability of a number of drugs by controlling their movement into, and out of, cells. The active transport systems P-gp and OATP play an important role in drug elimination. The activity of these transport systems is controlled, in part, by genetic factors; however, drugs and foods also influence the activity of these systems. It appears that interference with P-gp or OATP, either as upregulation or inhibition, may affect plasma drug concentrations by altering intestinal absorption, proximal renal-tubular excretion or biliary excretion. Overall, the net bioavailability of a drug or substance is affected by the relative contributions of cellular efflux (P-gp) and influx (OATP) mechanisms and to what extent these systems are active during phases of uptake and absorption versus removal and excretion from the body. Many of the drugs and foods that affect active drug transport activity are known to interact with the cytochrome P450 enzyme system; therefore, the net effect of concomitant drug administration is complex. One must now consider the impact of metabolism (CYP-mediated drug biotransformation), P-gp-mediated drug efflux and OATP-mediated uptake when making assessments of drug absorption and distribution.
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PMID:The role of P-glycoprotein and organic anion-transporting polypeptides in drug interactions. 1611 72

According to recent epidemiological reports, almost 40% of American population use complimentary and alternative medicine (CAM) during their lifetime. Patients detected with HIV or cancer often consume herbal products especially St. John's wort (SJW) for antidepressants in combination with prescription medicines. Such self-administered herbal products along with prescribed medicines raise concerns of therapeutic activity due to possible drug-herbal interactions. P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) together constitute a highly efficient barrier for many orally absorbed drugs. Available literature, clinical reports and in vitro studies from our laboratory indicate that many drugs and herbal active constituents are substrates for both P-gp and CYP3A4. Results from clinical studies and case reports indicate that self-administered SJW reduce steady state plasma concentrations of amitriptyline, cyclosporine, digoxin, fexofenadine, amprenavir, indonavir, lopinavir, ritonavir, saquinavir, benzodiazepines, theophyline, irinotecan, midazolan and warfarin. This herbal agent has been also reported to cause bleeding and unwanted pregnancies when concomitantly administered with oral contraceptives. Most of these medicinal agents and SJW are substrates for P-gp and/or CYP3A4. In vitro studies from our laboratory suggest that short-term exposure with pure herbal agents such as hypericin, kaempferol and quercetin or extract of SJW resulted in higher uptake or influx of ritonavir and erythromycin. Hypericin, kaempferol and quercetin also caused a remarkable inhibition of cortisol metabolism with the percent intact cortisol values of 64.58%, 89.6% and 90.1%, respectively, during short-term in vitro experiments. Conversely, long-term exposure of herbal agents (hyperforin, kaempferol and quercetin) showed enhanced expression of CYP3A4 mRNA in Caco-2 cells. In another study, we observed that long-term exposure of hypericin, kaempferol, quercetin and silibinin resulted in higher MDR-1 mRNA expression in Caco-2 cells. Therefore, herbs can pharmacokinetically act as inhibitors or inducers. Medicinal agents that are substrates P-gp-mediated efflux and/or CYP-mediated metabolism are likely to be potential candidates for drug-herbal interactions. The duration of exposure of cells/healthy volunteers/animals to herbals appears to be critical for drug-herbal interaction. An increase in plasma drug concentration is possible during concomitant administration of SJW and prescribed drugs. In contrast, prolonged intake of herbal supplement followed by drug administration may result in subtherapeutic concentrations. Therefore, clinical implications of such drug herbal interactions depend on a variety of factors such as dose, frequency and timing of herbal intake, dosing regimen, route of drug administration and therapeutic range. In vitro screening techniques will play a major role in identifying possible herb-drug interactions and thus create a platform for clinical studies to emerge. Mechanisms of drug-herbal interaction have been discussed in this review article.
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PMID:MDR- and CYP3A4-mediated drug-herbal interactions. 1644 30

Clinical findings indicate that co-administration of the isoxazolyl-penicillin flucloxacillin with cyclosporine may reduce the plasma concentrations of cyclosporine. We have explored in the present study if induction of cytochrome P450 3A4 or P-glycoprotein may offer a mechanistic explanation of the observed effects. Flucloxacillin is neither an inhibitor nor a substrate of drug metabolizing cytochrome P450 isoenzymes (CYP3A4, 1A2, 2C9, 2C19 and 2D6) or P-glycoprotein as shown by an in vitro assay for CYP inhibition, a fluorescent indicator assay for P-glycoprotein inhibition and a functional P-glycoprotein ATPase assay. However, incubation of human LS 180 colorectal adenocarcinoma cells with flucloxacillin led to a dose-dependent induction of MDR1 as well as of CYP3A4 mRNA, which was also confirmed in primary human hepatocytes. At high concentrations, flucloxacillin activated the human Pregnane-X-Receptor, PXR, a ligand-dependent transcription factor that is the target of many drugs that induce CYP3A4, with consequences for the metabolism of other drugs. Liver microsomes from control rats or rats, which received for 3 consecutive days 100 mg/kg of oral flucloxacillin, were used to study the metabolism and metabolite pattern of midazolam, a model substrate of CYP 3A4. There was a trend towards a higher intrinsic microsomal clearance of midazolam using microsomes from flucloxacillin treated rats. In addition, there was a significant increase in the formation of the principal midazolam metabolites 1-hydroxy midazolam, 4-hydroxy midazolam and 1,4-dihydroxy midazolam as compared to controls. These findings indicate that flucloxacillin has the potential to induce expression of both CYP3A4 as well as P-glycoprotein, most likely through activation of the nuclear hormone receptor PXR. This would offer an explanation for the observed clinical drug-drug interactions between the antibiotic and cyclosporine.
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PMID:Induction of cytochrome P450 3A4 and P-glycoprotein by the isoxazolyl-penicillin antibiotic flucloxacillin. 1647 2

There is wide variability in the response of individuals to standard doses of drug therapy. This is an important problem in clinical practice, where it can lead to therapeutic failures or adverse drug reactions. Polymorphisms in genes coding for metabolising enzymes and drug transporters can affect drug efficacy and toxicity. Pharmacogenetics aims to identify individuals predisposed to a high risk of toxicity and low response from standard doses of anti-cancer drugs. This review focuses on the clinical significance of polymorphisms in drug-metabolising enzymes (cytochrome P450 [CYP] 2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, dihydropyrimidine dehydrogenase, uridine diphosphate glucuronosyltransferase [UGT] 1A1, glutathione S-transferase, sulfotransferase [SULT] 1A1, N-acetyltransferase [NAT], thiopurine methyltransferase [TPMT]) and drug transporters (P-glycoprotein [multidrug resistance 1], multidrug resistance protein 2 [MRP2], breast cancer resistance protein [BCRP]) in influencing efficacy and toxicity of chemotherapy. The most important example to demonstrate the influence of pharmacogenetics on anti-cancer therapy is TPMT. A decreased activity of TPMT, caused by genetic polymorphisms in the TPMT gene, causes severe toxicity with mercaptopurine. Dosage reduction is necessary for patients with heterozygous or homozygous mutation in this gene. Other polymorphisms showing the influence of pharmacogenetics in the chemotherapeutic treatment of cancer are discussed, such as UGT1A1*28. This polymorphism is associated with an increase in toxicity with irinotecan. Also, polymorphisms in the DPYD gene show a relation with fluorouracil-related toxicity; however, in most cases no clear association has been found for polymorphisms in drug-metabolising enzymes and drug transporters, and pharmacokinetics or pharmacodynamics of anti-cancer drugs. The studies discussed evaluate different regimens and tumour types and show that polymorphisms can have different, sometimes even contradictory, pharmacokinetic and pharmacodynamic effects in different tumours in response to different drugs. The clinical application of pharmacogenetics in cancer treatment will therefore require more detailed information of the different polymorphisms in drug-metabolising enzymes and drug transporters. Larger studies, in different ethnic populations, and extended with haplotype and linkage disequilibrium analysis, will be necessary for each anti-cancer drug separately.
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PMID:Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer. 1650 59

This review focuses on drug-drug interactions with three major groups of antimicrobial agents: macrolides (including azalides and ketolides), quinolones, which are widely used for the treatment of bacterial infections, and azoles, which are used for antifungal therapy. Macrolides and the ketolide telithromycin are potent inhibitors of CYP3A4 and thus interfere with the pharmacokinetics of many other drugs that are metabolised by this enzyme. In contrast, although closely related, azithromycin is not a cytochrome inhibitor. All quinolones form complexes with di- and trivalent cations and, therefore, the absorption of quinolones can be dramatically reduced when given concomitantly with mineral antacids, zinc or iron preparations. Ciprofloxacin exhibits an inhibitory potential for the cytochrome isoenzyme 1A2, resulting in an inhibition of theophylline metabolism. Other quinolones, such as levofloxacin or moxifloxacin, do not interfere with theophylline metabolism. The systemic azoles, such as ketoconazole, itraconazole, fluconazole and voriconazole, are inhibitors of CYP isoenzymes, such as CYP3A4, CYP2C9 and CYP2C19, to varying degrees. In addition, some are substrates of the MDR-1 gene product, P-glycoprotein. These features are the basis for most of the interactions occurring during azole therapy (e.g., in severely ill patients in the hospital who are treated with multiple drugs).
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PMID:Drug interactions during therapy with three major groups of antimicrobial agents. 1655 82

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


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