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 on the efflux of the 5-HT(1A) receptor agonist flesinoxan across the blood-brain barrier in vivo and in vitro was investigated. In vitro, the transport ratios (representing polarized transport) of flesinoxan (10 microg/ml) were 4.2 in the MDR1-transfected LLC-PK1 cell line, which could be inhibited by the Pgp modulators SDZ-PSC 833 and LY 335979 and 1.1 in the wild-type LLC-PK1 cell line after 4 h. Flesinoxan concentrations lower than 33 microg/ml were actively transported by Pgp, while at higher concentrations Pgp became saturated and transport in the MDR1-transfected cell line was comparable with the wild-type cell line. In the in vitro BBB co-culture model the transport ratio was 2.0 and was decreased to 1.0 in the presence of Pgp modulators. In vivo, the accumulation of flesinoxan in the brain at 3 h was much higher in the mdr1a(-/-) mice compared to mdr1a(+/+) mice (ratio 12.6 and 27.0 at dose levels of 3 mg/kg and 10 mg/kg respectively). In conclusion, both in vivo as well as in vitro results have demonstrated that Pgp is a limiting factor for the transport of the 5-HT(1A) receptor agonist flesinoxan into the CNS. This should be considered when its application in therapy is combined with other Pgp substrates.
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PMID:Active efflux of the 5-HT(1A) receptor agonist flesinoxan via P-glycoprotein at the blood-brain barrier. 1145 54

The atypical antipsychotic, clozapine, exerts superior efficacy in therapy-resistant schizophrenia, but unfortunately induces agranulocytosis with an incidence of 0.8 - 1 %. In this study, we investigated the cellular uptake of clozapine into human promyelocytic leukaemia HL-60 cells using HPLC with electrochemical detection. On incubation with 1.25 to 40 microM clozapine for 30 min, a saturable, energy- and temperature-dependent uptake process takes place (K m = 18.8 microM, k cat = 1.36 nmol/5 min/mg protein at 37 degrees C). This suggests membrane passage of clozapine by a carrier mechanism. 10 microM Indatraline, an inhibitor of dopamine, noradrenaline and serotonin (5-HT) reuptake, but not the selective 5-HT reuptake inhibitor fluvoxamine, markedly reduced the transport of clozapine by 62 %, whereas addition of 10 mM glucose to the incubation medium increased intracellular clozapine concentrations by 28 %. Since cyclosporine A, vinblastine or verapamil up to a final concentration of 10 microM did not alter the intracellular accumulation of clozapine, an involvement of P-glycoprotein seems to be unlikely. In summary, clozapine uptake into HL-60 cells meets criteria of an active unidirectional transport. Its molecular correlates remain to be established.
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PMID:Uptake of clozapine into HL-60 promyelocytic leukaemia cells. 1210 52

Permeability of the blood-brain barrier (BBB) is one of the factors determining the bioavailability of therapeutic drugs. The BBB only allows entry of lipophilic compounds with low molecular weights by passive diffusion. However, many lipophilic drugs show negligible brain uptake. They are substrates for transporters such as P-glycoprotein (P-gp), multidrug-resistance associated protein (MRP) and organic anion transporting polypeptides (OATPs). The action of these carrier systems results in rapid efflux of xenobiotics from the central nervous system (CNS). Classification of candidate drugs as substrates or inhibitors of such carrier proteins is of crucial importance in drug development. Positron emission tomography (PET) can play an important role in the screening process by providing in vivo information, after the putative drug has passed in vitro tests. Although radiolabeled probes for MRP and OATP function are not yet available, many radiotracers have been prepared to study P-glycoprotein function in vivo with PET. These include alkaloids ((11)C-colchicine), antineoplastic agents ((11)C-daunorubicin, (18)F-paclitaxel), modulators of L-type calcium channels ((11)C-(+/-)verapamil, (11)C-R(+)-verapamil), beta-adrenoceptor antagonists ((11)C-(S)-carazolol, (18)F-(S)-1'-fluorocarazolol, (11)C-carvedilol), serotonin 5-HT(1A) receptor antagonists ((18)F-MPPF), opioid receptor antagonists ((11)C-loperamide, (11)C-carfentanyl), and various (64)Cu-labeled copper complexes. Studies in experimental animals have indicated that it is possible to assess P-glycoprotein function in the BBB and its effect on the uptake and binding of drugs within the intact CNS, using suitable P-gp modulators labeled with positron emitters. Provided that radiopharmaceuticals (and P-gp modulators) can be developed for human use, several exciting fields of study may be explored, viz. (i) direct evaluation of the effect of modulators on the cerebral uptake of therapeutic drugs; (ii) assessment of mechanisms underlying drug resistance in epilepsy; (iii) examination of the role of the BBB in the pathophysiology of neurodegenerative and affective disorders; and (iv) exploration of the relationship between polymorphisms of transporter genes and the pharmacokinetics of test compounds within the CNS.
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PMID:PET Studies on P-glycoprotein function in the blood-brain barrier: how it affects uptake and binding of drugs within the CNS. 1513 71

To investigate the role of serotonin (5-HT), an important neurotransmitter and hormone/paracrine agent in the small intestine, in the transport activity of P-glycoprotein (P-gp), the intestinal transport of quinidine, a P-gp substrate, was examined in 5-HT-depleted rats prepared by intraperitoneal administration of p-chlorophenylalanine, a specific inhibitor of tryptophan hydroxylase in 5-HT biosynthesis. In the in vitro transport study, quinidine transport across rat jejunum was significantly enhanced in both the secretory and absorptive directions under 5-HT-depleted conditions, although the secretory transport was still predominant. The electrophysiological study suggested that the quinidine transport via passive diffusion was enhanced presumably through a paracellular route. This might be due to looser tight junctions under 5-HT-depleted conditions. The voltage-clamp technique clearly indicated that the secretory transport of quinidine through the transcellular pathway was also enhanced by the depletion of 5-HT. Furthermore, 5-HT depletion increased verapamil-sensitive secretory transport of quinidine in rat jejunum. These results indicate that the secretory transport of quinidine via P-gp was significantly enhanced under 5-HT-depleted conditions. The level of ATP, an energy source for functioning P-gp, wet weight of jejunum, and total protein level in rat jejunal mucosa were not changed by 5-HT depletion, but the expression of P-gp in the brush-border membrane of rat jejunum was significantly induced, which is partly responsible for the enhancement of P-gp activity under the 5-HT-depleted condition.
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PMID:Up-regulation of P-glycoprotein expression in small intestine under chronic serotonin-depleted conditions in rats. 1546 48

The permeability of the blood-brain barrier (BBB) is one of the factors determining the bioavailability of drugs in the brain. The BBB only allows passage of lipophilic drugs by passive diffusion. However, some lipophilic drugs hardly enter the brain. The transmembrane protein P-glycoprotein (P-gp) is one of the carrier systems that is responsible for transportation of drugs out of the brain. P-Glycoprotein affects the pharmacokinetics of many drugs and can be inhibited by administration of modulators or competitive substrates. Identification and classification of central nervous system (CNS) drugs as P-gp substrates or inhibitors are of crucial importance in drug development. Positron emission tomography (PET) studies can play an important role in the screening process as a follow-up of high-throughput in vitro assays. Several rodent studies have shown the potential value of PET to measure the effect of P-gp on the pharmacokinetics and brain uptake of radiolabeled compounds. P-Glycoprotein-mediated effects were observed for two 5-HT(1a) receptor ligands, [(18)F]MPPF vs. [carbonyl-(11)C]WAY100635. Under control conditions, the specific brain uptake of [(18)F]MPPF is five- to eightfold lower than that of [(11)C]WAY100635. After cyclosporin A (CsA) modulation, [(18)F]MPPF uptake in the rat brain increased five- to tenfold. Cerebral uptake of [carbonyl-(11)C]WAY100635 was also increased by modulation, but in general the increase was lower than that observed for [(18)F]MPPF (two- to threefold). Brain uptake of the beta-adrenergic receptor ligands [(11)C]carazolol and [(18)F]fluorocarazolol was increased in P-gp knockout mice and CsA-treated rats. Both the specific and nonspecific binding of [(18)F]fluorocarazolol were doubled by CsA. Cerebral uptake of [(11)C]carazolol in rats was much lower than that of [(18)F]fluorocarazolol and no specific binding was measured. After CsA modulation, the uptake of [(11)C]carazolol increased five- to sixfold, but this uptake was not receptor-mediated. Quantitative PET studies in rodents on P-gp functionality demonstrated a dose-dependent increase of radioligands after administration of CsA. Studies with [(11)C]verapamil and [(11)C]carvedilol showed that complete modulation was achieved at 50 mg/kg CsA. The distribution volume of [(11)C]carvedilol increased from 0.25 in the control study to 1.0 after full modulation with CsA. By quantitative PET measurement of P-gp function, the dose of modulators required to increase the concentration of CNS drugs may be determined, which may result in improved drug therapy.
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PMID:Positron emission tomography studies on binding of central nervous system drugs and P-glycoprotein function in the rodent brain. 1591 74

Some arylmethyloxyphenyl derivatives were prepared as simplified structures of analogous arylpiperazines with high affinity toward dopaminergic D(2) and serotonergic 5-HT(1A) receptors and inhibiting P-glycoprotein (P-gp). The compounds 5b and 8b displayed good P-gp inhibition activity measured as [(3)H]vinblastine transport inhibition in the Caco-2 cell monolayer and intracellular doxorubicin accumulation in MCF7/Adr cells by flow cytometry. Compounds 5b and 8b also inhibited, dose-dependently, ATP-ase activation induced by P-gp substrate vinblastine.
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PMID:Arylmethyloxyphenyl derivatives: small molecules displaying P-glycoprotein inhibition. 1706 79

Limited brain uptake of radioligands with otherwise optimal properties for imaging brain receptors can be improved by blocking the effect of P-glycoprotein (P-gp), an efflux pump at the blood-brain barrier. Using small animal positron emission tomography (PET), we investigated how P-gp and its blockade with Cyclosporin A (CsA) affect rodent brain uptake of [(11)C](R)-(-)-RWAY, a radioligand for brain 5-HT(1A) receptors. Brain uptake of radioactivity was compared in control and CsA-treated rats as well as P-gp knockout and wild type mice. Parent radioligand and radiometabolite in plasma and brain samples were determined at 30 min after injection of radioligand. PET binding potential (BP) was calculated with a reference tissue model. P-gp knockout mice had 2.5- and 2.8-fold greater brain uptake of [(11)C](R)-(-)-RWAY than wild type ones, measured by in vivo PET and ex vivo tissue sampling, respectively. Similarly, CsA increased rat brain uptake 4.9- and 5.3-fold, in vivo and ex vivo. In addition, CsA increased the plasma free fraction of [(11)C](R)-(-)-RWAY in rats by 2.7-fold. Although CsA increased brain uptake in wild type mice by 2.5-fold, it had no effect on plasma free fraction in knockout animals. Three radiometabolites of [(11)C](R)-(-)-RWAY were uniformly distributed in rat brain, suggesting they were inactive. CsA treatment increased brain uptake of [(11)C](R)-(-)-RWAY and only one of its radiometabolites. Regional rat brain BP increased 27-70% in the CsA-treated rats and the P-gp knockout mice. [(11)C](R)-(-)-RWAY is a P-gp substrate in rat and mouse. The effects of CsA in rats are mediated by both P-gp blockade and displacement of the radiotracer from plasma proteins. Studies with wild type and knockout mice showed that CsA affected only P-gp in this species.
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PMID:Effect of a P-glycoprotein inhibitor, Cyclosporin A, on the disposition in rodent brain and blood of the 5-HT1A receptor radioligand, [11C](R)-(-)-RWAY. 1711 22

Medications to address gastrointestinal disorders are among the most commonly dispensed somatic medications. The authors examine proton pump inhibitors, H(2) blockers, 5-HT(3) receptor-antagonists, and a few other drugs that are used to address this domain of medical concerns. The metabolic pathways, interactions with the P-glycoprotein transporter, and capabilities of inhibiting or inducing metabolic enzymes are elucidated for each drug. Specific drug-drug interactions with each agent are also detailed, including both psychotropic and non-psychotropic agents. Also, the article explores how different genotypic variants for specific cytochrome P450 enzymes have an impact on the effectiveness and likelihood of drug-drug interactions relating to specific gastro-intestinal medications.
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PMID:Gastrointestinal medications. 1720 56

The intestinal absorption characteristics and the efflux mechanisms of zolmitriptan, a new generation and highly selective 5-HT(1B/1D) receptor agonist used in the acute oral treatment of migraine, were investigated. A human intestinal cell line, Caco-2, was used as an in-vitro model of the intestinal mucosa to assess transepithelial transport of zolmitriptan. In the Caco-2 cells, the absorptive transport of zolmitriptan was pH dependent and the transport was enhanced at weakly alkali pH on the apical side. No concentration dependence and saturation were observed for the apical-to-basolateral and basolateral-to-apical transport of zolmitriptan at a concentration of 0.1-10 mM. The permeability ratio value was about 1.5-2.6 at a concentration of 0.1-2.0 mM. Inhibition experiments using verapamil, nifedipine and nimodipine as inhibitors were studied and indicated that P-glycoprotein participated in the transport of zolmitriptan. Inhibition of the Na+-H+ exchanger with amiloride resulted in a significant increase in absorption and a slight inhibition in secretion. This suggests that the Na+-H+ exchanger may be involved in the transport of zolmitriptan. The results indicated that the transport of zolmitriptan was mediated by both passive diffusion and active transport. A series of drug-drug interaction experiments were carried out between zolmitriptan and some drugs that may be co-administrated with zolmitriptan in the clinic. The results indicated that flunarizine, cetirizine, propranolol and atenolol potently decreased both the apical-to-basolateral and basolateral-to-apical transport rate of zolmitriptan. Cimetidine and aspirin slightly inhibited the apical-to-basolateral transport of zolmitriptan, but significantly decreased the basolateral-to-apical transport of zolmitriptan. Thus, the absorption drug-drug interactions should be considered when these drugs are co-administrated with zolmitriptan in the clinic.
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PMID:Transport characteristics of zolmitriptan in a human intestinal epithelial cell line Caco-2. 1752 30

We investigated the relationships between functional genetic variants of the 5-HT(2C) receptor and multidrug-resistant protein (MDR1), coding for P-glycoprotein, and second generation antipsychotic (SDA)-induced weight gain among 108 female schizophrenic patients treated with olanzapine or risperidone for up to 4 months. No significant differences in -759C/T allelic and genotype variants of 5-HT(2C) were found between patients who gained more than 7% of their initial weight compared with those who gained less. Haplotype-based analysis of two MDR1 loci, exon 21 G2677T and exon 26 C3435T, revealed a slightly lower representation of the G2677/C3435 haplotype in the >or=7% group. In the subgroup of patients treated with risperidone, we found borderline overrepresentation of 2677T, significant overrepresentation of 3435T variant and borderline overrepresentation of 2677T/3435T haplotype the >or=7% group, whereas G2677/C3435 haplotype was found to be less represented in the >or=7% group. Our data indicate a nonsignificant role of 759C/T 5-HT(2C) in SDA-induced weight gain, and a stronger influence of the MDR1 G2677T and C3435T polymorphisms on risperidone-induced weight gain in female schizophrenic patients. 3435T and 2677T MDR1 variants, both associated with lower P-gp function, might predispose to higher risperidone accessibility to the brain that would lead to stronger effects, including weight gain.
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PMID:The influence of 5-HT(2C) and MDR1 genetic polymorphisms on antipsychotic-induced weight gain in female schizophrenic patients. 1871 76


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