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)

The role of P-glycoprotein in secretion of indinavir metabolites produced by CYP3A4 was evaluated in Caco-2 cells expressing CYP3A4. Metabolism of indinavir by CYP3A4 expressing Caco-2 cells grown on filters resulted in the formation of N-dealkylation products (M5 and M6) and hydroxylation of indinavir, which were preferentially secreted into the apical compartment. Apical secretion of the metabolites was inhibited by cyclosporin A (CsA) with all three classes of metabolites showing similar sensitivity to CsA, suggesting that they are all secreted by the same pathway. M6 stimulated P-glycoprotein (Pgp)-ATPase activity in a concentration-dependent manner. This stimulation was inhibited by the Pgp-specific monoclonal antibody C219. A method was developed to specifically inhibit Pgp using the monoclonal antibody UIC2 to determine whether Pgp efflux accounts for a significant proportion of the apical secretion of indinavir metabolites. UIC2 recognizes an extracellular transient conformational epitope that is stabilized by some Pgp substrates or by ATP depletion. Incubation of Caco-2 cells with UIC2 in the presence of 1 microM CsA resulted in 50 to 80% inhibition of Pgp-mediated vinblastine efflux, with no significant inhibition observed by UIC2 or CsA alone. Inhibition of Pgp in CYP3A4-expressing Caco-2 cells by UIC2 and 1 microM CsA resulted in a significant decrease in the apical secretion of M6, M5, and OH-indinavir and an increase in the amount of the metabolites secreted in the basolateral compartment and retained in the cytosol. These results are consistent with a role of Pgp in elimination of CYP3A4-generated metabolites and indicate that even relatively polar metabolites may be secreted from the cell by Pgp.
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PMID:P-glycoprotein-mediated efflux of indinavir metabolites in Caco-2 cells expressing cytochrome P450 3A4. 1140 58

CPT-11 belongs to the class of topoisomerase I inhibitors, and it acts as a prodrug of SN-38, which is approximately 100-1000-fold more cytotoxic than the parent drug. CPT-11 has shown a broad spectrum of antitumor activity in preclinical models as well as clinically, with responses observed in various disease types including colorectal, lung, cervical, and ovarian cancer. The pharmacokinetics and metabolism of CPT-11 are extremely complex and have been the subject of intensive investigation in recent years. Both CPT-11 and SN-38 are known in an active lactone form and an inactive carboxylate form, between which an equilibrium exists that depends on the pH and the presence of binding proteins. CPT-11 is subject to extensive metabolic conversion by various enzyme systems, including esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as well as CYP3A4, which forms several pharmacologically inactive oxidation products. Elimination routes of CPT-11 also depend on the presence of drug-transporting proteins, notably P-glycoprotein and canalicular multispecific organic anion transporter, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. Strategies to individualize CPT-11 administration schedules based on patient differences in enzyme or protein expression or by coadministration of specific agents modulating side effects are under way and may ultimately lead to more selective chemotherapeutic use of this agent.
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PMID:Clinical pharmacokinetics and metabolism of irinotecan (CPT-11). 1148 91

Sister of P-glycoprotein (SPGP) is the major hepatic bile salt export pump (BSEP). BSEP/SPGP expression varies dramatically among human livers. The potency and hierarchy of bile acids as ligands for the farnesyl/bile acid receptor (FXR/BAR) paralleled their ability to induce BSEP in human hepatocyte cultures. FXR:RXR heterodimers bound to IR1 elements and enhanced bile acid transcriptional activation of the mouse and human BSEP/SPGP promoters. In FXR/BAR nullizygous mice, which have dramatically reduced BSEP/SPGP levels, hepatic CYP3A11 and CYP2B10 were strongly but unexpectedly induced. Notably, the rank order of bile acids as CYP3A4 inducers and activators of pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR) closely paralleled each other but was markedly different from their hierarchy and potency as inducers of BSEP in human hepatocytes. Moreover, the hepatoprotective bile acid ursodeoxycholic acid, which reverses hydrophobic bile acid hepatotoxicity, activates PXR and efficaciously induces CYP3A4 (a bile-metabolizing enzyme) in primary human hepatocytes thus providing one mechanism for its hepatoprotection. Because serum and urinary bile acids increased in FXR/BAR -/- mice, we evaluated hepatic transporters for compensatory changes that might circumvent the profound decrease in BSEP/SPGP. We found weak MRP3 up-regulation. In contrast, MRP4 was substantially increased in the FXR/BAR nullizygous mice and was further elevated by cholic acid. Thus, enhanced hepatocellular concentrations of bile acids, due to the down-regulation of BSEP/SPGP-mediated efflux in FXR nullizygous mice, result in an alternate but apparent compensatory up-regulation of CYP3A, CYP2B, and some ABC transporters that is consistent with activation of PXR/SXR by bile acids.
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PMID:Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. 1150 73

The pharmacokinetics and pharmacodynamics of tacrolimus were evaluated in the pediatric recipients of living-related liver transplant. The mean clearance for tacrolimus was estimated with large interindividual variability and was shown to change as a function of days after operation. The therapeutic blood concentration of tacrolimus ranges were concerned from nearly 10 to 20 ng/ml. We have examined whether the expression levels of the intestinal absorptive barriers, MDR1 gene product P-glycoprotein and cytochrome P450 IIIA4(CYP3A4), correlate with the trough levels of orally administered tacrolimus in a recipient of small bowel transplant for 4 months. Both the MDR1 and CYP3A4 mRNA levels changed markedly through out this period. The tacrolimus concentration/dose ratio correlated well with the mRNA expression level of MDR1, but not CYP3A4. Intestinal P-glycoprotein rather than CYP3A4 is a good probe to predict the intraindividual variation in the tacrolimus pharmacokinetics.
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PMID:[Therapeutic drug monitoring of immunosuppresants]. 1151 26

1. UK-343,664 is a potent and specific PDE5 inhibitor. Following single oral doses to human volunteers, it exhibited non-proportional pharmacokinetics over the dose range 30-800 mg. Over this 27-fold dose range, Cmax and AUCt increased 247- and 287-fold respectively. The half-life (4-6 h) was similar at all doses. No systemic exposure was quantifiable at doses <10 mg. 2. UK-343,664 is a lipophilic molecule (log D7.4 = 3.1) and as such is expected to be cleared mainly by metabolism. Based on studies with expressed human P450 enzymes it was concluded that the metabolism of UK-343,664 was predominantly mediated by CYP3A4. With a moderate Km = 76 microM for this enzyme, saturation of first-pass metabolism alone was considered unlikely to account for the non-proportional pharmacokinetics. 3. UK-343,664 showed high affinity for P-glycoprotein in vitro, with a Km = 7.3 microM. In transport studies in LLC-PK1 cell monolayers transfected with P-glycoprotein, UK343,664 showed marked polarized transport which was concentration dependent. 4. The high affinity of UK-343,664 for P-glycoprotein is considered to be the primary source of the non-proportional pharmacokinetic profile observed in man.
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PMID:Potential role for P-glycoprotein in the non-proportional pharmacokinetics of UK-343,664 in man. 1156 32

The considerable overlap in the substrate selectivity and tissue localization of CYP3A and P-glycoprotein has led to the hypothesis that this transporter and enzyme pair act as a coordinated absorption barrier against xenobiotics. A historical perspective on the investigation of this interactive alliance is given, starting from the understanding of the role of intestinal metabolism in explaining cyclosporine clinical data. Several animal studies using mdr1a-/- knockout mice have demonstrated P-glycoprotein's importance in limiting drug absorption and decreasing bioavailability. Human clinical studies investigating the importance of intestinal CYP3A and P-glycoprotein through inhibition or induction of these proteins have provided further evidence of this interaction. Recent in vitro studies using CYP3A4-expressing Caco-2 cells are reported. These studies reveal that the role of P-glycoprotein in the intestine extends beyond simply limiting parent drug absorption but also includes increasing the access of drug to metabolism by CYP3A through repeated cycles of absorption and efflux.
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PMID:The drug efflux-metabolism alliance: biochemical aspects. 1157 92

This review describes the pharmacokinetics of the major drugs used for the treatment of inflammatory bowel disease. This information can be helpful for the selection of a particular agent and offers guidance for effective and well tolerated regimens. The corticosteroids have a short elimination half-life (t1/2beta) of 1.5 to 4 hours, but their biological half-lives are much longer (12 to 36 hours). Most are moderate or high clearance drugs that are hepatically eliminated, primarily by cytochrome P450 (CYP) 3A4-mediated metabolism. Prednisone and budesonide undergo presystemic elimination. Any disease state or comedication affecting CYP3A4 activity should be taken into account when prescribing corticosteroids. Depending on the preparation used, 10 to 50% of an oral or rectal dose of mesalazine is absorbed. Rapid acetylation in the intestinal wall and liver (t1/2beta 0.5 to 2 hours) and transport probably by P-glycoprotein affect mucosal concentrations of mesalazine, which apparently determine clinical response. Any clinical condition influencing the release and topical availability of mesalazine might modify its therapeutic potential. Metronidazole has high (approximately 90%) oral bioavailability, with hepatic elimination characterised by a t1/2beta of 6 to 10 hours and a total clearance of about 4 L/h/kg. Ciprofloxacin is largely excreted unchanged both renally (about 45% of dose) and extrarenally (25%), with a relatively short t1/2beta (3.5 to 7 hours). Thus, renal function affects the systemic availability of ciprofloxacin. Both mercaptopurine and its prodrug azathioprine are metabolised to active compounds (6-thioguanine nucleotides; 6-TGN) by hypoxanthine-guanine phosphoribosyltransferase and to inactive metabolites by the polymorphically expressed thiopurine S-methyltransferase (TPMT) and xanthine oxidase. Patients with low TPMT activity have a higher risk of developing haemopoietic toxicity. Both mercaptopurine and azathioprine have a short t1/2beta (1 to 2 hours), but the t1/2beta of 6-TGN ranges from 3 to 13 days. Therapeutic response seems to be related to 6-TGN concentration. Almost complete bioavailability has been observed after intramuscular and subcutaneous administration of methotrexate, which is predominantly (85%) excreted as unchanged drug with a t1/2beta of up to 50 hours. Thus, renal function is the major determinant for disposition of methotrexate. Cyclosporin is slowly and incompletely absorbed. It is extensively metabolised by CYP3A4/5 in the liver and intestine (median t1/2beta and clearance 7.9 hours and 0.46 L/h/kg, respectively), and inhibitors and inducers of CYP3A4 can modify response and toxicity. Infliximab is predominantly distributed to the vascular compartment and eliminated with a t1/2beta between 10 and 14 days. No accumulation was observed when it was administered at intervals of 4 or 8 weeks. Methotrexate may reduce the clearance of infliximab from serum.
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PMID:Pharmacokinetic considerations in the treatment of inflammatory bowel disease. 1170 60

In an open-label, randomized, multicenter, multiple-dose pharmacokinetic study, we determined the steady-state pharmacokinetics of amprenavir with and without coadministration of indinavir, nelfinavir, or saquinavir soft gel formulation in 31 human immunodeficiency virus type 1-infected subjects. The results indicated that amprenavir plasma concentrations were decreased by saquinavir soft gel capsule (by 32% for area under the concentration-time curve at steady state [AUC(ss)] and 37% for peak plasma concentration at steady state [C(max,ss)]) and increased by indinavir (33% for AUC(ss)). Nelfinavir significantly increased amprenavir minimum drug concentration at steady state (by 189%) but did not affect amprenavir AUC(ss) or C(max,ss). Nelfinavir and saquinavir steady-state pharmacokinetics were unchanged by coadministration with amprenavir compared with the historical monotherapy data. Concentrations of indinavir, coadministered with amprenavir, in plasma decreased in both single-dose and steady-state evaluations. The changes in amprenavir steady-state pharmacokinetic parameters, relative to those for amprenavir alone, were not consistent among protease inhibitors, nor were the changes consistent with potential interactions in CYP3A4 metabolism or P-glycoprotein transport. No dose adjustment of either protease inhibitor in any of the combinations studied is needed.
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PMID:Pharmacokinetic study of human immunodeficiency virus protease inhibitors used in combination with amprenavir. 1170 66

Pharmacokinetic interactions involving anti-infective drugs may be important in the intensive care unit (ICU). Although some interactions involve absorption or distribution, the most clinically relevant interactions during anti-infective treatment involve the elimination phase. Cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 are the major isoforms responsible for oxidative metabolism of drugs. Macrolides (especially troleandomycin and erythromycin versus CYP3A4), fluoroquinolones (especially enoxacin, ciprofloxacin and norfloxacin versus CYP1A2) and azole antifungals (especially fluconazole versus CYP2C9 and CYP2C19, and ketoconazole and itraconazole versus CYP3A4) are all inhibitors of CYP-mediated metabolism and may therefore be responsible for toxicity of other coadministered drugs by decreasing their clearance. On the other hand, rifampicin is a nonspecific inducer of CYP-mediated metabolism (especially of CYP2C9, CYP2C19 and CYP3A4) and may therefore cause therapeutic failure of other coadministered drugs by increasing their clearance. Drugs frequently used in the ICU that are at risk of clinically relevant pharrmacokinetic interactions with anti-infective agents include some benzodiazepines (especially midazolam and triazolam), immunosuppressive agents (cyclosporin, tacrolimus), antiasthmatic agents (theophylline), opioid analgesics (alfentanil), anticonvulsants (phenytoin, carbamazepine), calcium antagonists (verapamil, nifedipine, felodipine) and anticoagulants (warfarin). Some lipophilic anti-infective agents inhibit (clarithromycin, itraconazole) or induce (rifampicin) the transmembrane transporter P-glycoprotein, which promotes excretion from renal tubular and intestinal cells. This results in a decrease or increase, respectively, in the clearance of P-glycoprotein substrates at the renal level and an increase or decrease, respectively, of their oral bioavailability at the intestinal level. Hydrophilic anti-infective agents are often eliminated unchanged by renal glomerular filtration and tubular secretion, and are therefore involved in competition for excretion. Beta-lactams are known to compete with other drugs for renal tubular secretion mediated by the organic anion transport system, but this is frequently not of major concern, given their wide therapeutic index. However, there is a risk of nephrotoxicity and neurotoxicity with some cephalosporins and carbapenems. Therapeutic failure with these hydrophilic compounds may be due to haemodynamically active coadministered drugs, such as dopamine, dobutamine and furosemide, which increase their renal clearance by means of enhanced cardiac output and/or renal blood flow. Therefore, coadministration of some drugs should be avoided, or at least careful therapeutic drug monitoring should be performed when available. Monitoring may be especially helpful when there is some coexisting pathophysiological condition affecting drug disposition, for example malabsorption or marked instability of the systemic circulation or of renal or hepatic function.
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PMID:Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions. 1173 5

The bulk of characterized xenobiotic defense and disposition is conferred by the abundant enzymes cytochrome P450 3A4 and P-glycoprotein. Although expressed in many tissues, these enzymes are most abundant in the liver and intestine and seem to share most substrates and inhibitors, with the apparent synergy between these two promiscuous enzymes asserted because of their extensive overlap of substrates and shared tissue location. Since the broad-spectrum tolerance to lipophilic compounds of various sizes naturally results in a similar pattern of substrate/inhibitor recognition, the cause or mechanism of many drug/drug and drug/herb interactions can be difficult to determine. These two seemingly indiscriminate enzymes, however, do not share some unique inhibitor selectivity. Particularly, we show various potent CYP3A4 inhibitors that do not affect P-gp active transport function. Remarkably, we have also identified several compounds-valinomycin, norverapamil, reserpine, nobiletin, emetine, gallopamil, fluphenazine-that uniquely inhibit P-gp function with affinities comparable to benchmark P-gp inhibitors despite a lack of effect on CYP3A4 function at physiologically relevant concentrations. Indeed, valinomycin inhibits P-gp with an IC(50) similar to cyclosporin A yet apparently does not affect CYP3A4 function, and emetine and nobiletin are also specific for interaction with P-gp. Additionally, norverapamil and reserpine have, respectively, a 60- and 40-fold preference for inhibition of P-gp over CYP3A4. Some striking structural analogies among these compounds are discussed. These distinguishing qualities of substrate recognition between CYP3A4 and P-gp should reveal nuances of active-site architecture unique to each and could serve as tools to probe for the specific discernment of P-gp-mediated drug/drug or drug/herb interactions. Learning more about binding distinctions and quantitative activity relationships of substrate/inhibitor interactions with these two enzymes and the differences between them may indicate how they recognize such a wide variety of molecules as substrates (and/or inhibitors). Moreover, identification of specific inhibitors will allow the determination of which enzyme is responsible for drug interactions and/or the extent of contribution in a multiple exposure situation.
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PMID:Quantitative distinctions of active site molecular recognition by P-glycoprotein and cytochrome P450 3A4. 1174 42


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