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 HMG-CoA reductase inhibitors (statins) are effective in both the primary and secondary prevention of ischaemic heart disease. As a group, these drugs are well tolerated apart from two uncommon but potentially serious adverse effects: elevation of liver enzymes and skeletal muscle abnormalities, which range from benign myalgias to life-threatening rhabdomyolysis. Adverse effects with statins are frequently associated with drug interactions because of their long-term use in older patients who are likely to be exposed to polypharmacy. The recent withdrawal of cerivastatin as a result of deaths from rhabdomyolysis illustrates the clinical importance of such interactions. Drug interactions involving the statins may have either a pharmacodynamic or pharmacokinetic basis, or both. As these drugs are highly extracted by the liver, displacement interactions are of limited importance. The cytochrome P450 (CYP) enzyme system plays an important part in the metabolism of the statins, leading to clinically relevant interactions with other agents, particularly cyclosporin, erythromycin, itraconazole, ketoconazole and HIV protease inhibitors, that are also metabolised by this enzyme system. An additional complicating feature is that individual statins are metabolised to differing degrees, in some cases producing active metabolites. The CYP3A family metabolises lovastatin, simvastatin, atorvastatin and cerivastatin, whereas CYP2C9 metabolises fluvastatin. Cerivastatin is also metabolised by CYP2C8. Pravastatin is not significantly metabolised by the CYP system. In addition, the statins are substrates for P-glycoprotein, a drug transporter present in the small intestine that may influence their oral bioavailability. In clinical practice, the risk of a serious interaction causing myopathy is enhanced when statin metabolism is markedly inhibited. Thus, rhabdomyolysis has occurred following the coadministration of cyclosporin, a potent CYP3A4 and P-glycoprotein inhibitor, and lovastatin. Itraconazole has been shown to increase exposure to simvastatin and its active metabolite by at least 10-fold. Pharmacodynamically, there is an increased risk of myopathy when statins are coprescribed with fibrates or nicotinic acid. This occurs relatively infrequently, but is particularly associated with the combination of cerivastatin and gemfibrozil. Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring. Knowledge of the pharmacokinetic properties of the statins should allow the avoidance of the majority of drug interactions. If concurrent therapy with known inhibitors of statin metabolism is necessary, the patient should be monitored for signs and symptoms of myopathy or rhabdomyolysis and the statin should be discontinued if necessary.
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PMID:Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. 1203 92

Dietary constituents (e.g., in grapefruit juice; NaCl) and phytochemicals (e.g., St. John's wort) are important agents modifying drug metabolism and transport and thereby contribute to interindividual variability in drug disposition. Most of these drug-food interactions are due to induction or inhibition of P-glycoprotein and/or CYP3A4. Preliminary data indicate that piperine, a major component of black pepper, inhibits drug-metabolizing enzymes in rodents and increases plasma concentrations of several drugs, including P-glycoprotein substrates (phenytoin and rifampin) in humans. However, there are no direct data whether piperine is an inhibitor of human P-glycoprotein and/or CYP3A4. We therefore investigated the influence of piperine on P-glycoprotein-mediated, polarized transport of digoxin and cyclosporine in monolayers of Caco-2 cells. Moreover, by using human liver microsomes we determined the effect of piperine on CYP3A4-mediated formation of the verapamil metabolites D-617 and norverapamil. Piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC(50) values of 15.5 and 74.1 microM, respectively. CYP3A4-catalyzed formation of D-617 and norverapamil was inhibited in a mixed fashion, with K(i) values of 36 +/- 8 (liver 1)/49 +/- 6 (liver 2) and 44 +/- 10 (liver 1)/77 +/- 10 microM (liver 2), respectively. In summary, we showed that piperine inhibits both the drug transporter P-glycoprotein and the major drug-metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first-pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concentrations of P-glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally.
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PMID:Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. 1213 Jul 27

1. The use of herbal products to treat a wide range of conditions is rising rapidly, leading to increased intake of phytochemicals. Recent studies revealed potentially fatal interactions between herbal remedies and traditional drugs. 2. In transplant patients, self-medication with St John's wort (Hypericum perforatum) has led to a drop in plasma levels of the immunosuppressant drug cyclosporine, causing tissue rejection. 3. Intake of St John's wort increases the expression of intestinal P-glycoprotein and the expression of CYP3A4 in the liver and intestine. The combined up-regulation in intestinal P-glycoprotein and hepatic and intestinal CYP3A4 impairs the absorption and stimulates the metabolism of cyclosporine, leading to subtherapeutic plasma levels. The St John's wort component, hyperforin, contributes to the induction of CYP3A4. 4. St John's wort also enhances the metabolism of other CYP3A4 substrates including the protease inhibitors indinavir and nevirapine, oral contraceptives, and tricyclic antidepressants such as amitriptyline. 5. Other herbal remedies with the potential to modulate cytochrome P450 activity and thus participate in interactions with conventional drugs include Milk thistle, Angelica dahurica, ginseng, garlic preparations, Danshen and liquorice. 6. Herbal products are currently not subject to the rigorous testing indispensable for conventional drugs. However, if potential drug interactions are to be predicted, it is essential that the ability of herbal products to interfere with drug-metabolizing enzyme systems is fully established.
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PMID:Pharmacokinetic interactions between herbal remedies and medicinal drugs. 1216 Apr 80

The bioavailability of structurally unrelated drugs is limited by active secretion via the multidrug resistance gene (MDR1) product P-glycoprotein (Pgp) from enterocyte into lumen as well as intestinal metabolism by cytochrome P450 IIIA4 (CYP3A4). In the present study, we analyzed whether genetic polymorphism of the MDR1 had some influence on the intestinal expression levels of Pgp and CYP3A4 and the tacrolimus concentration/dose ratio over the first postoperative days in recipients of living-donor liver transplantation (LDLT). Genotyping assays were performed for the major 10 polymorphisms in the MDR1 gene by the polymerase chain reaction-restriction enzyme length polymorphism method. The allele frequencies of variations at five positions were almost comparable with those in the former studies in Caucasians and Japanese, but there was no variation at the other five positions. Although no polymorphism correlated with the intestinal expression of MDR1 mRNA or the tacrolimus concentration/dose ratio in the LDLT recipients, the C3435T polymorphism significantly affected the intestinal expression level of CYP3A4 mRNA as follows; 3435C/C>3435C/T (P < 0.05 vs. 3435C/C)>3435T/T (P < 0.01 vs. 3435C/C). Therefore, the identified polymorphisms including C3435T in the MDR1 gene were indicated to have no influence on the intestinal expression level of Pgp or the tacrolimus concentration/dose ratio in the recipients of LDLT. On the other hand, the C3435T polymorphism of MDR1 was suggested to correlate with the enterocyte expression of CYP3A4 rather than Pgp linking unknown genetic variation in CYP3A4 gene.
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PMID:C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation. 1217 10

N-[(3-fluorophenyl)methyl]glycyl-N-[3-[((3-aminophenyl)sulfonyl)- 2-(aminophenyl)amino]-(1S,2S)-2-hydroxy-1-(phenylmethyl)propyl]- 3-methyl-L-valinamide (DPC 681, DPC(1)) on oral coadministration with ritonavir (RTV) in rats caused a significant increase in systemic exposure to DPC. Following a single oral dose of [(14)C]DPC with and without RTV pretreatment in rats, and subsequent analysis of whole-body sections, prepared at 1 and 7 or 8 h postdose, using whole-body autoradiography showed an increase in radioactivity in tissues (e.g., brain, and testes) upon coadministration. The distribution of radioactivity in the brain parenchyma and ventricles was different, such that the concentration of radioactivity was greater in cerebrospinal fluid (CSF) than in central nervous system. Thus, the use of CSF concentration of the total radioactivity as a surrogate for brain penetration would result in an overestimation. DPC was determined to be metabolized prominently by rCYP3A4. The increased tissue exposure to DPC in rats could largely be attributed to inhibition of CYP3A1/2 by RTV. DPC was also a good substrate for P-glycoprotein (Pgp), with K(m) of 4 microM and V(max) of 13 pmol/min. The Pgp-mediated transport of DPC across Caco-2 cells was readily saturated at >or=10 microM and was inhibited significantly by RTV at 5 to 10 microM. The data above and the reported RTV concentrations suggested that both the Pgp and CYP3A4 inhibition by RTV may play a significant role in enhancing the systemic and tissue exposure to DPC in humans.
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PMID:Interaction of ritonavir on tissue distribution of a [(14)c]L-valinamide, a potent human immunodeficiency virus-1 protease inhibitor, in rats using quantitative whole-body autoradiography. 1238 20

The human pregnane X receptor (hPXR) plays a key role in the regulation of both drug metabolism and efflux by inducing the expression of CYP3A4 and MDR1 gene. Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, we identified seven novel splicing variants of hPXR in tissue from a single human liver. The expression of hPXR-related transcripts in the liver samples of 15 Caucasian individuals was subsequently determined by RT-PCR assays. The pattern of expression levels of these transcripts varied among liver samples. These results suggest that the hPXR is expressed as several different transcripts in liver tissues, apparently due to alternative as well as defective gene splicing. Furthermore, because this study provides the possibility of interindividual differences in hPXR transcript profiles, these alternative splicings for hPXR may largely contribute to the interindividual variability in CYP3A4 and P-glycoprotein induction.
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PMID:Identification of the novel splicing variants for the hPXR in human livers. 1241 60

Cyclosporin, an immunosuppressant with a narrow therapeutic window, is a substrate for both CYP3A4 and P-glycoprotein (Pgp). Quercetin is an inhibitor of CYP3A4 and a modulator of Pgp. This study aimed to measure the effect of quercetin on the absorption and disposition of cyclosporin in pigs and rats. Cyclosporin (Sandimmune, 10 mg/kg) was orally administered with and without a concomitant dose of quercetin (50 mg/kg) to pigs and rats. Cyclosporin concentrations in blood samples were determined by a specific monoclonal fluorescence polarization immunoassay. The pharmacokinetic parameters were calculated by noncompartmental analysis using WINNONLIN. A paired Student's t-test was conducted for statistical comparison. A study using the everted intestinal sac was carried out to evaluate the effect of quercetin on the function of intestinal Pgp. The coadministration of quercetin significantly decreased cyclosporin AUC(0-3) (area under the concentration-time curve from time zero to 3 h) by 56% and AUC(0-t) (area under the concentration-time curve from time zero to the last point) by 43% in pigs and rats, respectively, indicating that the coadministration of quercetin significantly decreased cyclosporin oral bioavailability. However, the inverted sac study showed that quercetin significantly inhibited the function of intestinal Pgp. It is suggested that concurrent use of quercetin or quercetin-containing dietary supplement or herbs with cyclosporin or other medications whose absorption and metabolism are mediated by Pgp and/or CYP3A4 should require close monitoring.
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PMID:Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats. 1242 82

P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-glycoprotein plays a significant role in drug absorption and disposition. Because of its localisation, P-glycoprotein appears to have a greater impact on limiting cellular uptake of drugs from blood circulation into brain and from intestinal lumen into epithelial cells than on enhancing the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space. However, the relative contribution of intestinal P-glycoprotein to overall drug absorption is unlikely to be quantitatively important unless a very small oral dose is given, or the dissolution and diffusion rates of the drug are very slow. This is because P-glycoprotein transport activity becomes saturated by high concentrations of drug in the intestinal lumen. Because of its importance in pharmacokinetics, P-glycoprotein transport screening has been incorporated into the drug discovery process, aided by the availability of transgenic mdr knockout mice and in vitro cell systems. When applying in vitro and in vivo screening models to study P-glycoprotein function, there are two fundamental questions: (i) can in vitro data be accurately extrapolated to the in vivo situation; and (ii) can animal data be directly scaled up to humans? Current information from our laboratory suggests that in vivo P-glycoprotein activity for a given drug can be extrapolated reasonably well from in vitro data. On the other hand, there are significant species differences in P-glycoprotein transport activity between humans and animals, and the species differences appear to be substrate-dependent. Inhibition and induction of P-glycoprotein have been reported as the causes of drug-drug interactions. The potential risk of P-glycoprotein-mediated drug interactions may be greatly underestimated if only plasma concentration is monitored. From animal studies, it is clear that P-glycoprotein inhibition always has a much greater impact on tissue distribution, particularly with regard to the brain, than on plasma concentrations. Therefore, the potential risk of P-glycoprotein-mediated drug interactions should be assessed carefully. Because of overlapping substrate specificity between cytochrome P450 (CYP) 3A4 and P-glycoprotein, and because of similarities in P-glycoprotein and CYP3A4 inhibitors and inducers, many drug interactions involve both P-glycoprotein and CYP3A4. Unless the relative contribution of P-glycoprotein and CYP3A4 to drug interactions can be quantitatively estimated, care should be taken when exploring the underlying mechanism of such interactions.
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PMID:Role of P-glycoprotein in pharmacokinetics: clinical implications. 1248 79

P-glycoprotein (P-gp), the most extensively studied ATP-binding cassette transporter, functions as a biological barrier by extruding toxic substances and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-gp plays a significant role in drug absorption and disposition. Like cytochrome P450 enzymes, inhibition and induction of P-gp have been reported as the causes of drug-drug interactions. Because many prototypic inhibitors and inducers affect both CYP3A4 and P-gp, many drug interactions caused by these inhibitors and inducers involve these two systems. Clinically, it is very difficult to quantitatively differentiate P-gp-mediated drug interactions versus CYP3A4-mediated drug interactions, unless their relative contributions can be accurately estimated. Therefore, care should be exercised when interpreting drug interaction data and exploring the underlying mechanisms of drug interactions.
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PMID:Drug-drug interaction mediated by inhibition and induction of P-glycoprotein. 1253 74

Drug interactions are frequently the result of altered activity of the mechanism(s) responsible for drug elimination. These include drug metabolism mediated by a select group of cytochrome P450 enzymes (CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2) and drug transporters (P-glycoprotein). Adverse drug interactions can result from induction (loss of therapeutic benefit) or inhibition (increased toxicity from excessive effect) of drug elimination. CYPs and P-glycoprotein are discussed individually with regards to their characteristics, frequently prescribed drug substrates, inducers and inhibitors, and important adverse drug events. The potential for important drug interactions can be predicted based on the properties of the causative agent (oral bioavailability, mechanism of elimination, seriousness of adverse event) and the interacting agent. Consequently, drug interactions can be prevented by avoiding concomitant administration of interacting substances or possibly implementing alternative therapeutic strategies. Furthermore, susceptibility to adverse events depends not only on the interacting substances, but also on the patient and the method of drug administration. Commonly prescribed drugs that are unlikely to cause a drug interaction involving CYPs or P-glycoprotein are also discussed.
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PMID:A basic conceptual and practical overview of interactions with highly prescribed drugs. 1258 77


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