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)

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

We previously demonstrated that P-glycoprotein and MRP2 contribute to the secretory transport of grepafloxacin in the small intestine. Although inhibitors of these secretory transporters increased absorptive transport of grepafloxacin, secretory transport was not altered in Caco-2 cells, as determined by a conventional Transwell method. Because the value of the permeability coefficient of grepafloxacin is high, permeation through the unstirred water layer (UL) might be the rate-limiting step. To examine the possibility that the UL effect may mask the involvement of membrane transporters in the transport of drug with high permeability in Caco-2 cells, transport experiments were performed by agitating the experimental solution to decrease the thickness of the UL, and by lowering the temperature to decrease permeation via active transporters. Under these conditions, the UL effect was not rate limiting, and the inhibitory effects of transporter modulators were reflected in the apparent permeability as a decrease in secretory transport as well as an increase in absorptive transport. In conclusion, it was demonstrated that the UL can be the rate-limiting factor for transport of drugs with high membrane permeability in Caco-2 cells. When the UL affects the apparent permeability in an experimental apparatus in vitro, careful analysis is required to evaluate the contributions of transporters from the apparent permeability of drugs.
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PMID:Experimental demonstration of the unstirred water layer effect on drug transport in Caco-2 cells. 1282 Jan 54

Despite the efficiency of the present polytherapies against AIDS, HIV replication continues indicating difficulties in drug adherence, drug-drug interactions, resistance issues, and the existence of reservoirs or sanctuaries for the virus. Moreover, most of the current FDA-approved HIV protease inhibitors (PIs) display disadvantageous physicochemical and pharmacological properties such as low water solubility, low oral bioavailability and/or low level of penetration into the HIV sanctuaries resulting from their in vivo binding to the plasma proteins and to the Multi-Drug-Resistant P-glycoprotein, their rapid metabolization and inactivation by the liver cytochrome P450 enzymes. To overcome these suboptimal pharmacokinetics, high daily doses must be ingested, which complicate patient adherence to the prescribed regimen and contribute to the appearance of serious long-term metabolic complications and to the decrease of the viral treatment outcome. Another attractive alternative aimed at improving the safety, pharmacokinetics, and therapeutic potency of the current PIs is to modify these PIs into pharmacologically inactive prodrugs which are converted in vivo into their parent active drug. The present review is dedicated to the different prodrug approaches, including the "lipophilic", "hydrophilic", "active transport" and "double-drug" prodrug strategies, which have been applied more particularly to the current HIV PIs used in clinic. Among the strategies explored up to now, the most successful one was the "hydrophilic" prodrug approach which has led to the discovery of fosamprenavir, a phosphate ester prodrug of amprenavir, which has reached phase III clinical trials. This success gives strong support for the search of PI prodrugs as a therapeutic alternative in addition to the development of new and well-tolerated PIs.
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PMID:Prodrugs of HIV protease inhibitors. 1287 Nov 95

Previous investigations directed to the determination of the P-glycoprotein (Pgp) expression in aquatic organisms have indicated the possibility of the multixenobiotic resistance mechanism (MXR) induction as a response to organic pollution. However, in numerous cases no significant and/or no clear relationship between Pgp contents and pollution level was detected. Concerning these discrepancies the results of an extensive, 3-year study of the Pgp mediated MXR induction in the selected freshwater (Dreissena polymorpha) and marine (Mytilus galloprovincialis) bivalves are presented here. The main goals of the study were to ascertain the rate-dynamic, level, as well as the possible usability of MXR in environmental biomonitoring. Since the primary result of MXR induction should be the decreased intracellular accumulation of xenobiotics, the determination of MXR induction was performed using the measurement of Pgp transport activity. We measured the accumulation or the efflux rate of the model Pgp substrate rhodamine B (RB) in gills of the mussels previously exposed to pollution. The study was performed in several steps: from the exposure experiments in laboratory, using model inducers rhodamine 123 (R123) and water extract of Diesel-2 oil (D2), to the final in situ testing in real environmental conditions. Our results confirmed that Pgp activity is induced/induces according to the level of pollution, and that 4-days period was already long enough for the significant induction and deinduction of MXR activity. However, the inducibility of Pgp transport activity was significantly limited--the maximal level of induction obtained in this study resulted in 50-60% lower RB accumulation in the gills of induced specimens (laboratory or in situ exposed to pollution), when compared to control, non-induced animals. The obtained level of Pgp related MXR induction, resulting in halfway lesser accumulation of a model pollutant (RB), extrapolated to the similar scenario with toxic xenobiotics may have significant environmental relevance. However, our results also suggest that for the use of the MXR as a relevant biomarker the Pgp transport activity should be measured along with the determination of DNA, mRNA or/and protein expression. Based on the data from this study several factors that may have had critical influence on the effectiveness and the level of MXR induction are additionally discussed.
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PMID:Inducibility of the P-glycoprotein transport activity in the marine mussel Mytilus galloprovincialis and the freshwater mussel Dreissena polymorpha. 1456 58

In our previous papers we described the ability of methylxanthine pentoxifylline (PTX) to depress the P-glycoprotein (P-gp) mediated multidrug resistance (MDR) of the mouse leukemic cell line L1210/VCR. Other methylxanthines like caffeine and theophylline were found to be ineffective in this respect. In the present paper we have analysed the capability of 25 methylxanthines to depress MDR of L1210/VCR cells. These methylxanthines structurally differ in substituents located in positions N1, N3, N7 and C8. The results indicate that for an effective reversal of P-gp mediated MDR of our cells the existence of a longer polar substituent in the position N1 plays a crucial role. The elongation of the substituent in the positions N3 and N7 (from methyl to propyl) increases and in the position C8 (from H to propyl) decreases the efficacy of xanthines to reverse the vincristine resistance of L1210/VCR cells. The multiple linear regression for effectiveness of methylxanthines in reversal of P-gp mediated MDR of L1210/VCR cells (expressed as respective IC(50r) values) has been computed, with molar weight: M(w), molar volume: V(M), molar refractivity: R(M), crystal density: d and partition coefficient n-octanol/water: logP as descriptors. A high intercorrelation of M(W), V(M) and R(M) was found for the tested group of methylxanthines indicating that only one of these parameters is necessary for testing a potential correlation. The best fit in the multiple linear regression was obtained for R(M) applied together with d and logP and resulted in a QSAR model given by the following equation: IC(50r)=-[(32.3+/-7.2)x10(-3)xR(M)]+[(10.1+/-2.3)xd]+[(0.74+/-0.10)xlogP]-[10.5+/-3.2]. Model revealed that: (i) the molar refractivity influences the effectiveness of xanthine positively; (ii) the crystal density and partition coefficient influence the MDR reversal effectiveness of xanthine negatively.
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PMID:Reversal of P-glycoprotein mediated vincristine resistance of L1210/VCR cells by analogues of pentoxifylline. A QSAR study. 1475

Irinotecan (CPT-11) is a semisynthetic derivative of camptothecin, an alkaloid extracted from the Chinese plant Camptotheca acuminata. It bears a bis-piperidine moiety and was selected for its water solubility and promising preclinical antitumor activity in in vitro and in vivo models. The target of drugs of the camptothecin family is DNA topoisomerase I, a nuclear enzyme involved in the relaxation of the DNA double helix required for replication and transcription activities. They stabilize the enzyme-DNA complex and prevent the religation of the single-strand breaks created by the enzyme, which are converted to double-strand breaks upon the collision with a replication fork during the S-phase. Resistance to irinotecan appears not to be mediated by P-glycoprotein, but by qualitative and/or quantitative alterations of its target, topoisomerase I, or by alterations occurring downstream of this interaction. As with all camptothecin derivatives, irinotecan contains a lactone ring that can be spontaneously and reversibly hydrolyzed to a carboxylate open ring form, which predominates at neutral and alkaline pH and is inactive on topoisomerase I-DNA complexes. Irinotecan is, in fact, much less active than its metabolite SN-38 and is generally considered as a prodrug of this compound. The carboxylesterase which carries out this conversion is preferentially active on the lactone form of irinotecan and directly generates the lactone form of SN-38, which may explain the superiority of irinotecan over SN-38 in vivo. Further metabolism of SN-38 to a beta-glucuronide conjugate is a major pathway of detoxification and plays an important role in determining irinotecan toxicity in the clinical setting. Other metabolic pathways of irinotecan involve oxidations occurring on the bis-piperidine rings, which are carried out by cytochrome P450. Irinotecan has shown an important activity in advanced and metastatic colorectal carcinoma and is now used for this indication in several countries, with two different recommended schedules: weekly administration of 125 mg/m(2) with a 2-week drug-free interval every 4 administrations or 3-weekly administration of 350 mg/m(2), a dose that can be increased to 500 mg/m(2) with the support of antidiarrhetics. Other possible indications of irinotecan include lung and cervix cancer, which are presently under investigation. The dose-limiting toxicity of irinotecan is mainly diarrhea, which occurs 7-10 days after treatment and can be life-threatening when associated with neutropenia, another frequent side effect. High-dose loperamide has shown good efficacy for treating this diarrhea and has allowed an increase in irinotecan doses tolerated by patients. The pharmacokinetics of irinotecan are characterized by a 2- or 3-compartment decay, with a terminal half-life of about 10 h, a total volume of distribution of 150 l/m(2) and a total plasma clearance of 15 l/h/m(2). SN-38 AUC is only a small fraction of that of irinotecan (2-4%) and SN-38 is eliminated from plasma with a half-life of about 12 h. SN-38 glucuronide is present in plasma at higher concentrations than SN-38 and is eliminated at the same rate. APC, produced by the action of cytochrome P450, isoenzyme 3A4, is present in plasma at concentrations close to those of irinotecan itself. Only a small fraction of irinotecan and its metabolites is eliminated in urine and a higher proportion in the bile, with an enterohepatic cycle of SN-38 glucuronide and SN-38. Significant relationships have been established between the AUCs of both irinotecan and SN-38 and hematological and intestinal toxicities, suggesting a potential use for monitoring of this drug.
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PMID:Pharmacology of irinotecan. 1498 54

To evaluate the intestinal permeability of poorly water-soluble compounds, it is of importance to completely dissolve them in a medium and to avoid precipitation during experiments. This study was undertaken to find an agent possessing a high-solubilizing capacity and exhibiting minimal modulating impact on membrane integrity and absorption systems such as passive diffusion and carrier-mediated permeation. Phenytoin dissolution was compared in the presence of seven solubilizing agents at concentrations of 1, 2, or 5% using a centrifugation method. The capacity to dissolve phenytoin was great in beta-cyclodextrin (beta-CD) and hydroxypropyl beta-cyclodextrin, followed by Tween 80. Those of methanol, dimethyl sulfoxide, dimethyl acetoamide, and polyethylene glycol 400 were much lower than expected. One percent beta-CD did not alter the absorption of fluorescein isothiocyanate-dextran 4,000 or the release of protein and lactate dehydrogenase into in situ loop contents, suggesting that 1% beta-CD had no significant impact on the integrity of the intestinal membrane. One percent beta-CD also did not alter the absorption of caffeine, ceftibuten, or rhodamine 123 from in situ jejunal loops, indicating no interference with passive diffusion and active transports mediated by a peptide transporter and P-glycoprotein. In conclusion, 1% beta-CD is a suitable solubilizing agent for evaluating in situ intestinal absorption of poorly water-soluble compounds.
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PMID:Beta-cyclodextrin as a suitable solubilizing agent for in situ absorption study of poorly water-soluble drugs. 1526 50

R1481 is a sub-type selective muscarinic receptor antagonist with the potential treatment of overactive bladder. R1481 presents two challenges for drug development. The first is the viscous semi-solid nature of the active pharmaceutical ingredient (API). The second challenge is the poor oral bioavailability of this water soluble, metabolically stable compound due to low intestinal permeability, and the P-glycoprotein (P-gp) efflux mechanism. Vitamin E TPGS is reported by others to enhance bioavailability by increasing the solubility of active compounds and by inhibiting P-gp in the intestine. In this report, compatibility of R1481 in Capmul MCM-based formulations with and without vitamin E TPGS is summarized. Review of accelerated stability studies of oral formulations led to the identification of a soft gelatin capsule formulation using neat Capmul MCM as an acceptable formulation for Phase 1 clinical studies. Soft gelatin capsules (5 mg strength) were manufactured with and without the addition of vitamin E TPGS. Clinical data show that vitamin E TPGS does not improve systemic exposure of R1481 in humans.
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PMID:Pre-clinical and clinical evaluation of solution and soft gelatin capsule formulations for a BCS class 3 compound with atypical physicochemical properties. 1529 82

The ability to maintain cellular volume is an important general physiological function. Swelling induced by hypotonic stress results in the opening of channels, through which ions exit with accompanying water loss (regulatory volume decrease, RVD). RVD has been shown to occur in mammalian sperm, primarily through the opening of quinine-sensitive potassium channels. However, as yet, direct evidence for the participation of anion channels in sperm RVD has been lacking. The chloride channel type ClC-3 is believed to be involved in RVD in other cell types. Using electronic cell sizing for cell volume measurement, the following results were obtained. (i) The anion channel blockers 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), tamoxifen and 4,4'-diisothiocyanostilbene-2,2'-disulphonic acid (DIDS) increased hypotonic swelling in concentration-dependent fashion, whereas verapamil (P-glycoprotein inhibitor) had little effect. The most potent, NPPB and DIDS, blocked RVD without affecting cell membrane integrity at effective concentrations. (ii) When gramicidin was included to dissipate Na+/K+ gradients, major secondary swelling was observed under hypotonic conditions. This secondary swelling could be reduced by NPPB, and suppressed completely by replacing chloride in the medium with sulphate, an ion which does not pass through chloride channels. It was deduced that the initial hypotonic swelling activated an anion channel through which chloride ions could then enter freely down a concentration gradient, owing to the lack of a counter-gradient of potassium. (iii) Taurine, an osmolyte often involved in RVD, does not appear to play a role in sperm RVD because lengthy preincubation with taurine did not alter sperm RVD response. Our observations provide direct evidence that a chloride channel (possibly ClC-3) is involved in the process of volume regulation in mammalian sperm.
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PMID:Role of volume-stimulated osmolyte and anion channels in volume regulation by mammalian sperm. 1536 53

It has been reported that inhibition of the P-glycoprotein (P-gp) results in the improved absorption of P-gp substrate in the intestinal tract. In fact, the increased permeability of P-gp substrate across the intestinal epithelium was observed following inhibition of P-gp in in vitro experiments. To develop the formulation containing P-gp inhibitor and P-gp substrate for practical use, it is necessary to know whether the results obtained in the in vitro experiments are reproducible at whole body level. It is also important to find out the regional difference of the P-gp activity in the intestinal tract. In this study, we examined whether verapamil, a specific inhibitor of P-gp, improves the absorption of rhodamine123 (Rho123), a substrate of P-gp, from the jejunum, ileum, and colon of rats using the in situ loop method. The water content in the loop decreased during the experiment, resulting in a significant change of the Rho123 concentration in the loop. Thus, to accurately determine the absorption rate of Rho123, it was necessary to measure the water movement. It was found that there was a regional difference in the water movement, i.e., greatest in colon, followed by ileum. Verapamil did not change the water movement in any intestinal regions. When the concentration of Rho123 in the loop was corrected by water movement, the Rho123 clearance was in the order of ileum (1.15 microL/min/cm), colon (0.83 microL/min/cm) and jejunum (0.47 microL/min/cm). In the presence of verapamil, the Rho123 clearance was significantly increased at jejunum and ileum but not in colon (ileum: 2.08 microL/min/cm, colon: 1.14 microL/min/cm, jejunum: 1.28 microL/min/cm). These results suggest that P-gp inhibits the drug absorption in jejunum and ileum. From these results, it is possible to evaluate the role of P-gp and its regional difference in the in situ experiments. In particular, the inhibition of P-gp results in an increase in absorption of the P-gp substrate limited to jejunum and ileum.
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PMID:Regional difference in P-glycoprotein function in rat intestine. 1585 20


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