Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Having changed the landscape in the treatment of HIV infection, the functional efficacy of current protease inhibitors (PIs) remains limited by their pharmacokinetic and pharmacodynamic profiles. Complex metabolism by the cytochrome P450 system (particularly the 3A4 isoenzyme), action of membrane drug transporter elements (such as P-glycoprotein and multi-drug resistance-associated proteins) and activation of the nuclear receptor steroid xenobiotic receptor may alter exposures and compromise the antiretroviral activity of these drugs. These factors, as well as inadequate adherence, can facilitate the emergence of PI resistance and lead to regimen failure. Coadministration of ritonavir can enhance exposures of a primary PI by inhibiting CYP3A4 metabolism, P-glycoprotein activity and multi-drug resistance protein-1-mediated efflux. Adding ritonavir, however, is not without cost. Dyslipidaemia (possibly increasing the risk of cardiovascular events), gastrointestinal intolerance, multiple drug-to-drug interactions and activation of steroid xenobiotic receptor can all result and must be balanced against the pharmacokinetic improvement rendered by the addition of ritonavir. Understanding the pharmacological origins for the variations in exposures of PIs, both between and within patients, is important for the successful use of these agents.
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PMID:The role of pharmacological enhancement in protease inhibitor-based highly active antiretroviral therapy. 1260 63

Class III antiarrhythmic drugs, especially amiodarone (a broad-spectrum antiarrhythmic agent), have gained popularity for use in clinical practice in recent years. Other class III antiarrhythmic drugs include bretylium, dofetilide, ibutilide and sotalol. These agents are effective for the management of various types of cardiac arrhythmias both atrial and ventricular in origin. Class III antiarrhythmic drugs may interact with other drugs by two major processes: pharmacodynamic and pharmacokinetic interactions. The pharmacodynamic interaction occurs when the pharmacological effects of the object drug are stimulated or inhibited by the precipitant drug. Pharmacokinetic interactions can result from the interference of drug absorption, metabolism and/or elimination of the object drug by the precipitant drug. Among the class III antiarrhythmic drugs, amiodarone has been reported to be involved in a significant number of drug interactions. It is mainly metabolised by cytochrome P450 (CYP)3A4 and it is a potent inhibitor of CYP1A2, 2C9, 2D6 and 3A4. In addition, amiodarone may interact with other drugs (such as digoxin) via the inhibition of the P-glycoprotein membrane transporter system, a recently described pharmacokinetic mechanism of drug interactions. Bretylium is not metabolised; it is excreted unchanged in the urine. Therefore the interactions between bretylium and other drugs (including other antiarrhythmic drugs) is primarily through the pharmacodynamic mechanism. Dofetilide is metabolised by CYP3A4 and excreted by the renal cation transport system. Drugs that inhibit CYP3A4 (such as erythromycin) and/or the renal transport system (such as triamterene) may interact with dofetilide. It appears that the potential for pharmacokinetic interactions between ibutilide and other drugs is low. This is because ibutilide is not metabolised by CYP3A4 or CYP2D6. However, ibutilide may significantly interact with other drugs by a pharmacodynamic mechanism. Sotalol is primarily excreted unchanged in the urine. The potential for drug interactions due to hepatic enzyme induction or inhibition appears to be less likely. However, a number of drugs (such as digoxin) have been reported to interact with sotalol pharmacodynamically. If concurrent use of a class III antiarrhythmic agent and another drug cannot be avoided or no published studies for that particular drug interaction are available, caution should be exercised and close monitoring of the patient should be performed in order to avoid or minimise the risks associated with a possible adverse drug interaction.
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PMID:Potentially significant drug interactions of class III antiarrhythmic drugs. 1268 33

In vitro and clinical studies were conducted to characterize the potential of avasimibe, an acyl-CoA/cholesterol acyltransferase inhibitor to cause drug-drug interactions. Clinically, 3- and 6-fold increases in midazolam (CYP3A4 substrate) oral clearance were observed after 50 and 750 mg of avasimibe daily for 7 days, respectively. A 40% decrease in digoxin (P-glycoprotein substrate) area under the curve was observed with 750 mg of avasimibe daily for 10 days. In vitro studies were conducted to define the mechanisms of these interactions. Induction was observed in CYP3A4 activity and immunoreactive protein (EC50 of 200-400 nM) in primary human hepatocytes treated with avasimibe. Rifampin treatment yielded similar results. Microarray analysis revealed avasimibe (1 microM) increased CYP3A4 mRNA 20-fold, compared with a 23-fold increase with 50 microM rifampin. Avasimibe induced P-glycoprotein mRNA by about 2-fold and immunoreactive protein in a dose-dependent manner. Transient transfection assays showed that avasimibe is a potent activator of the human pregnane X receptor (hPXR) and more active than rifampin on an equimolar basis. Drug-drug interaction studies for CYP3A4 using pooled human hepatic microsomes and avasimibe at various concentrations, revealed IC50 values of 20.7, 1.6, and 3.1 microM using testosterone, midazolam, and felodipine as probe substrates, respectively. Our results indicate that avasimibe causes clinically significant drug-drug interactions through direct activation of hPXR and the subsequent induction of its target genes CYP3A4 and multiple drug resistance protein 1.
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PMID:Avasimibe induces CYP3A4 and multiple drug resistance protein 1 gene expression through activation of the pregnane X receptor. 1276 53

Pharmacogenetics focuses on intersubjects variation in therapeutic drug effects and toxicity depending on genetic polymorphisms. This is particularly interesting in oncology since anticancer drugs usually have a narrow margin of safety. Irinotecan [7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin] is used in cancer chemotherapy as a topoisomerase I inhibitor and it is characterised by a sometimes unpredictable severe toxicity. It is mostly intestinal with nausea, vomit and diarrhoea or haematologic with leuko-thrombocytopenia. Its complex metabolism involves many proteins. Human carboxylesterase isoforms 1 and 2 (hCE1, hCE2) activate irinotecan to its metabolite SN-38 (7-ethyl-10-hydroxycamptothecin); cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5) mediate the oxidation of the parental compound to irinotecan; uridino-glucuronosil transferase isoform 1A1 (UGT1A1) catalyses glucuronidation of SN-38; the multi-resistance protein isoform 2 (MRP2) allows the cellular excretion of the SN-38 glucuronide (SN-38G) and the multi-drug resistance gene (MDR1), encoding for P-glycoprotein, is responsible for the excretion of irinotecan from the cell. Polymorphic structures in the genes encoding for all these proteins have been described. In particular, the UGT1A1*28 allele has been associated with an increased toxicity after irinotecan chemotherapy. Classical parameters used in the clinic, such as body-surface area, have no longer a meaningful correlation with clinical outcome. Hence it emerges the importance of studying the individual genotype to predict the toxicity and efficacy of irinotecan and to individualise therapy. In this review, we summarise the new developments on the study of the pharmacogenetics of irinotecan, stressing its importance in drug cytotoxic effect.
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PMID:Pharmacogenetics of irinotecan. 1276 80

Key factors undergoing maturational changes accounting for differences in drug metabolism and disposition in the pediatric population compared with adults are reviewed. Gastric and duodenal pH, gastric emptying time, intestinal transit time, bacterial colonization and probably P-glycoprotein are important factors for drug absorption, whereas key factors explaining differences in drug distribution between the pediatric population and adults are membrane permeability, plasma protein concentration and plasma protein characteristics, endogenous substances in plasma, total body and extracellular water, fat content, regional blood flow and probably P-glycoprotein, mainly that present in the gut, liver and brain. As far as drug metabolism is concerned, important differences have been found in the pediatric population compared with adults both for phase I enzymes [oxidative (e.g. cytochrome CYP3A7 vs. CYP3A4 and CYP1A2), reductive and hydrolytic enzymes] and phase II enzymes (e.g. N-methyltransferases and glucuronosyltransferases). Finally, key factors undergoing maturational changes accounting for differences in renal excretion in the pediatric population compared with adults are glomerular filtration and tubular secretion. It would be important to generate information on the developmental aspects of renal P-glycoprotein and of other renal transporters as done and still being done with the different isozymes involved in drug metabolism.
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PMID:Drug metabolism and disposition in children. 1280 68

"Reaction phenotyping" studies were performed with eletriptan (ETT) to determine its propensity to interact with coadministered medications. Its ability to serve as a substrate for human P-glycoprotein (P-gp) was also investigated since a central mechanism of action has been proposed for this "triptan" class of drug. In studies with a characterized bank of human liver microsome preparations, a good correlation (r2 = 0.932) was obtained between formation of N-desmethyl eletriptan (DETT) and CYP3A4-catalyzed testosterone 6 beta-hydroxylation. DETT was selected to be monitored in our studies since it represents a significant ETT metabolite in humans, circulating at concentrations 10 to 20% of those observed for parent drug. ETT was metabolized to DETT by recombinant CYP2D6 (rCYP2D6) and rCYP3A4, and to a lesser extent by rCYP2C9 and rCYP2C19. The metabolism of ETT to DETT in human liver microsomes was markedly inhibited by troleandomycin, erythromycin, miconazole, and an inhibitory antibody to CYP3A4, but not by inhibitors of other major P450 enzymes. ETT had little inhibitory effect on any of the P450 enzymes investigated. ETT was determined to be a good substrate for human P-gp in vitro. In bidirectional transport studies across LLC-MDR1 and LLC-Mdr1a cell monolayers, ETT had a BA/AB transport ratio in the range 9 to 11. This finding had significance in vivo since brain exposure to ETT was reduced 40-fold in Mdr1a+/+ relative to Mdr1a-/- mice. ETT metabolism to DETT is therefore catalyzed primarily by CYP3A4, and plasma concentrations are expected to be increased when coadministered with inhibitors of CYP3A4 and P-gp activity.
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PMID:Eletriptan metabolism by human hepatic CYP450 enzymes and transport by human P-glycoprotein. 1281 62

Variability in CYP3A (CYP3A4/5) and P-glycoprotein (human MDR1 gene product) activity underlies interindividual differences in oral cyclosporine (CsA) bioavailability. Racial differences in polymorphic expression of CYP3A5 and MDR1 may explain observed interracial variability in oral bioavailability. Our objective was to evaluate the effect of CYP3A5 and MDR1 polymorphic expression on CsA oral disposition. Steady-state plasma concentration profiles (n = 19) were sampled in renal transplant recipients receiving concentration-adjusted CsA maintenance therapy. CsA plasma concentrations were measured by fluorescence polarization immunoassay. CYP3A5 and MDR1 genotypes were determined by real-time polymerase chain reaction. Noncompartmental pharmacokinetic analysis and nonlinear mixed-effects modeling (NONMEM) were performed to assess the effect of genotype on CsA pharmacokinetics. MDR1 C3435T genotype was identified as the best predictor of CsA systemic exposure. CsA oral clearance was significantly higher in subjects who carried at least one 3435T allele compared to homozygous wild-type individuals (40.0 +/- 2.2 vs. 26.4 +/- 3.1 L/h, p = 0.007). MDR1 C3435T genotype accounted for 43% of the interindividual variability of CsA oral clearance in the study population after accounting for interoccasion variability. The authors were unable to independently assess whether CYP3A5 correlated with any CsA pharmacokinetic parameter since all CYP3A5 nonexpressors were also 3435T allele carriers. MDR1 3435T allele carriers have enhanced oral clearance compared to individuals with the CC genotype. The frequency of the 3435T allele is lower in African Americans compared to Caucasians. Thus, the MDR1 C3435T genotype offers a potential mechanistic basis to explain interracial differences in CsA oral bioavailability. Further studies are needed to explore the relationship between CYP3A5 and MDR1 genotype and phenotype.
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PMID:The effect of CYP3A5 and MDR1 polymorphic expression on cyclosporine oral disposition in renal transplant patients. 1281 18

The antituberculosis drug rifampicin (rifampin) induces a number of drug-metabolising enzymes, having the greatest effects on the expression of cytochrome P450 (CYP) 3A4 in the liver and in the small intestine. In addition, rifampicin induces some drug transporter proteins, such as intestinal and hepatic P-glycoprotein. Full induction of drug-metabolising enzymes is reached in about 1 week after starting rifampicin treatment and the induction dissipates in roughly 2 weeks after discontinuing rifampicin. Rifampicin has its greatest effects on the pharmacokinetics of orally administered drugs that are metabolised by CYP3A4 and/or are transported by P-glycoprotein. Thus, for example, oral midazolam, triazolam, simvastatin, verapamil and most dihydropyridine calcium channel antagonists are ineffective during rifampicin treatment. The plasma concentrations of several anti-infectives, such as the antimycotics itraconazole and ketoconazole and the HIV protease inhibitors indinavir, nelfinavir and saquinavir, are also greatly reduced by rifampicin. The use of rifampicin with these HIV protease inhibitors is contraindicated to avoid treatment failures. Rifampicin can cause acute transplant rejection in patients treated with immunosuppressive drugs, such as cyclosporin. In addition, rifampicin reduces the plasma concentrations of methadone, leading to symptoms of opioid withdrawal in most patients. Rifampicin also induces CYP2C-mediated metabolism and thus reduces the plasma concentrations of, for example, the CYP2C9 substrate (S)-warfarin and the sulfonylurea antidiabetic drugs. In addition, rifampicin can reduce the plasma concentrations of drugs that are not metabolised (e.g. digoxin) by inducing drug transporters such as P-glycoprotein. Thus, the effects of rifampicin on drug metabolism and transport are broad and of established clinical significance. Potential drug interactions should be considered whenever beginning or discontinuing rifampicin treatment. It is particularly important to remember that the concentrations of many of the other drugs used by the patient will increase when rifampicin is discontinued as the induction starts to wear off.
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PMID:Pharmacokinetic interactions with rifampicin : clinical relevance. 1288 88

The major aim of this study was to investigate the CYP3A4 metabolism and polarized transport of ropivacaine and its metabolite 2',6'-pipecoloxylidide (PPX) in tissue specimens from the human small and large intestine. Ropivacaine has been shown to be effective in the treatment of ulcerative colitis in human colon. This study was conducted using a modified Ussing-chamber technique with specimens from jejunum, ileum and colon collected from 11 patients. The local kinetics of ropivacaine and PPX were assessed from their concentration-time profiles in mucosal and serosal compartments. The permeability (P(app)) in the absorptive direction for both ropivacaine and PPX increased regionally in the order jejunum < ileum < colon. Ropivacaine was not found to be subjected to any carrier-mediated intestinal efflux. However, the CYP3A4 metabolite left the human enterocyte in a polarized manner and both the extent of CYP3A4 metabolism of ropivacaine and the extrusion of its metabolite to the mucosal chamber were more efficient in jejunum than in ileum. P-glycoprotein was probably not involved in the metabolite extrusion. No other metabolite than PPX was found. This in-vitro study with human intestinal tissues provides new mechanistic insights into regional transport and metabolism of drugs.
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PMID:Regional transport and metabolism of ropivacaine and its CYP3A4 metabolite PPX in human intestine. 1290 53

The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, has been shown to reduce major cardiovascular events in both primary and secondary prevention, and statins became one of the most widely prescribed classes of drugs throughout the world. Previously, statins have been well tolerated and have shown favorable safety profiles. However, the voluntary withdrawal of cerivastatin from the market because of a disproportionate number of reports of rhabdomyolysis-associated deaths drew attention to the pharmacokinetic profile of statins, which may possibly have been related to serious drug-drug interactions. Pitavastatin (NK-104, previously called itavastatin or nisvastatin, Kowa Company Ltd., Tokyo) is a novel, fully synthetic statin, which has a potent cholesterol-lowering action. The short-term and long-term lipid-modifying effects of pitavastatin have already been investigated in subjects with primary hypercholesterolemia, heterozygous familial hypercholesterolemia, hypertriglyceridemia, and type-2 diabetes mellitus accompanied by hyperlipidemia. Within the range of daily doses from 1 to 4 mg, the efficacy of pitavastatin as a lipid-lowering drug seems to be similar, or potentially superior, to that of atorvastatin. According to the results of pharmacokinetic studies, pitavastatin showed favorable and promising safety profile; it was only slightly metabolized by the cytochrome P450 (CYP) system, its lactone form had no inhibitory effects on the CYP3A4-mediated metabolism of concomitantly administered drugs; P-glycoprotein-mediated transport did not play a major role in its disposition, and pitavastatin did not inhibit P-glycoprotein activity. It could be concluded that pitavastatin could provide a new and potentially better therapeutic choice for lipid-modifying therapy than do the currently available statins. The efficacy and safety of higher dose treatment, as well as its long-term effects in the prevention of coronary artery disease, should be further investigated.
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PMID:Pitavastatin: efficacy and safety profiles of a novel synthetic HMG-CoA reductase inhibitor. 1293 Dec 54


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