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)

Intestinal drug efflux mediated by P-glycoprotein and other ABC transporters is widely accepted as a reason for low or variable oral absorption. However, little is known about species and regional differences in P-glycoprotein so the functional and predictive relevance of observations made in cell models such as Caco-2 is uncertain. The aim of this study was to define the kinetics of drug efflux in rat and human intestinal tissues in vitro using the "reference" substrates digoxin and vinblastine. The expression and functional role of other ABC transporters in the transport of these compounds was also investigated. Saturable, verapamil-sensitive efflux of digoxin was observed in all intestinal regions. Apparent affinity of the efflux process varied within a relatively narrow range (50-92 microM), increasing in rat from small to large intestine. In contrast, maximal transporter activity varied over a 4- to 5-fold range with ileum > jejunum > colon. Similar regional differences in efflux were also observed with vinblastine. Maximal efflux levels were similar in Caco-2 and ileum for both substrates, suggesting that Caco-2 may quantitatively predict small intestinal drug efflux. Digoxin efflux kinetics was virtually identical in rat and human colon. Inhibitor studies showed that digoxin and vinblastine efflux in intestinal tissues was mediated by P-glycoprotein, although a minor component could be attributed to multidrug resistance-related protein (MRP)-like transporters in Caco-2. This study has analyzed the differential functional expression of drug efflux along the gastrointestinal tract. Such data will be critical in developing predictive models of P-glycoprotein-mediated efflux using information gathered from in vitro systems.
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PMID:Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia. 1116 Jun 47

Digoxin is a drug with a narrow therapeutic index, which is substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidneys. Whereas particle size, dissolution rate and lipophilic properties have been identified as determinants for absorption of digitalis glycosides, little is known about P-glycoprotein transport characteristics of digitalis glycosides such as digitoxin, alpha-methyldigoxin, beta-acetyldigoxin and ouabain. Using polarized P-glycoprotein-expressing cell lines we therefore studied whether these compounds are substrates of P-glycoprotein. Polarized transport of digitalis glycosides was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells (LLC-PK1 cells stably transfected with the human MDR1 P-glycoprotein). Inhibition of P-glycoprotein-mediated transport of these compounds in Caco-2 cells was determined using the cyclosporine analogue PSC-833 (valspodar) as inhibitor of P-glycoprotein. No polarized transport was observed for ouabain. However, basal-to-apical transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin was greater than apical-to-basal transport in Caco-2 and L-MDR1 cells. In Caco-2 cells net transport rates of these compounds were similar to those of digoxin (digoxin: 16.0+/-4.4%, digitoxin: 15.0+/-3.3%, beta-acetyldigoxin: 16.2+/-1.6%, alpha-methyldigoxin: 13.5+/-4.8%). Furthermore, polarized transport of these compounds could be completely inhibited by 1 microM PSC-833. In summary, these data provide evidence that not only digoxin, but also digitoxin, alpha-methyldigoxin and beta-acetyldigoxin are substrates of P-glycoprotein.
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PMID:P-glycoprotein-mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin. 1128 49

Sustained fetal tachyarrhythmia (> 180 bpm) is a potentially life-threatening condition for the unborn. Digoxin is commonly used as an initial monotherapy. Flecainide, sotalol, and verapamil are also used as a monotherapy or a combination therapy with digoxin. The treatment success rate with digoxin is about 50%. Presence of hydrops is associated with poor placental transfer of digoxin. Although transplacental pharmacotherapy has been available, it is a challenging task to maximize fetal drug exposure, while minimizing drug exposure of the mother. In addition, clear evidence behind drug of choice and treatment algorithm is lacking. Whereas prospective clinical studies with rigorous design remain to be seen, our knowledge on placental drug transport at a molecular level has been steadily increasing. For example, an ATP-dependent membrane protein, known as P-glycoprotein, is expressed in placenta, decreasing fetal exposure to maternal digoxin. Pharmacological manipulation of drug transporters may open a door to ultimate optimization of the transplacental pharmacotherapy.
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PMID:Transplacental treatment of fetal tachycardia: implications of drug transporting proteins in placenta. 1145 17

In the central nervous system, the primary targets of the human immunodeficiency virus-1 (HIV-1) are microglia, resulting in a disorder called HIV-1 dementia. P-glycoprotein (P-gp), a membrane-associated ATP-dependent efflux transporter, limits entry into the brain of numerous xenobiotics, including anti-HIV drugs (i.e., protease inhibitors). This project investigates the functional expression of P-gp in the endogenous immune cells of the brain, a parenchymal compartment not previously studied. We used a cell line (MLS-9) derived from rat microglia to study the transport of digoxin, a known P-gp substrate. Reverse transcriptase-polymerase chain reaction analysis detected mRNA for only mdr1b in MLS-9 cells, whereas both mdr1a and mdr1b mRNA were expressed in primary cultured microglia from which they were derived. Western blot analysis with the C219 antibody detected a single band at ~170 to 180 kDa in MLS-9 cells, which is the size previously reported for P-gp. Immunocytochemical analysis with the monoclonal antibodies C219, MRK16, and MAB-448 labeled P-gp protein along the plasma membrane and nuclear envelope of MLS-9 cells. [3H]Digoxin accumulation by monolayers of MLS-9 cells was significantly enhanced in the presence of any of several P-gp inhibitors (verapamil, cyclosporin A, quinidine, PSC 833), protease inhibitors (i.e., saquinavir, indinavir, and ritonavir), and sodium azide, an ATPase inhibitor. These results provide the first evidence for the functional expression of P-gp in microglia and imply that entry of pharmacological agents, including protease inhibitors, may be prevented within the brain parenchyma, as well as at the blood-brain barrier.
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PMID:Functional expression of P-glycoprotein in rat brain microglia. 1156 Oct 81

1. Inflammation is a pathophysiological event that has relevance for altered drug disposition in humans. Two functions of P-glycoprotein (P-gp) are hepatic drug elimination and prevention of drug entry into the central nervous system (CNS). Our objective was to investigate if localized CNS inflammation induced by Escherichia coli lipopolysaccharide (LPS) would modify mdr1a/P-gp expression and function in the brain and liver. 2. Our major finding was that the CNS inflammation in male rats produced a loss in the expression of mdr1a mRNA in the brain and liver that was maximal 6 h after intracranial ventricle (i.c.v.) administration of LPS. When (3)H-digoxin was used at discrete time points, as a probe for P-gp function in vivo, an increase in brain and liver (3)H-radioactivity and plasma level of parent digoxin was produced 6 and 24 h following LPS treatment compared to the saline controls. Digoxin disposition was similarly altered in mdr1a(+/+) mice but not in mdr1a(-/-) mice 24 h after administering LPS i.c.v. 3. In male rats, the biliary elimination of parent digoxin was reduced at 24 h (60%) and 48 h (40%) after LPS treatment and was blocked by the P-gp substrate cyclosporin A. An observed loss in CYP3A1/2 protein and organic anion transporting polypeptide 2 mRNA in the liver may make a minor contribution to digoxin elimination in male rats after LPS treatment. 4. Conditions which impose inflammation in the CNS produce dynamic changes in mdr1a/P-gp expression/function that may alter hepatic drug elimination and the movement of drugs between the brain and the periphery. The use of experimental models of brain inflammation may provide novel insight into the regulation of P-gp function in that organ.
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PMID:Downregulation of mdr1a expression in the brain and liver during CNS inflammation alters the in vivo disposition of digoxin. 1274 21

Digoxin and beta-methyldigoxin were evaluated pharmacokinetically in terms of P-glycoprotein (P-gp)-mediated drug interactions in rats. Evaluation was made by measuring the effects of a potent P-gp inhibitor (verapamil, cyclosporin A) on in vitro efflux transport of these compounds across the everted small intestine, on in situ absorption from the small intestine, and on in vivo total plasma clearance (CL(total)) as well as biliary and urinary excretions after intravenous administration. Both the intestinal efflux transport and absorption of beta-methyldigoxin were approximately 1.5-fold greater than those of digoxin, probably due to its higher lipophilicity. Addition of verapamil (300 microM) significantly decreased the intestinal efflux transport and increased the intestinal absorption of digoxin. In contrast, the influence of verapamil on beta-methyldigoxin was small. Intravenous cyclosporin A (30 mg/kg) significantly decreased in vivo CL(total) and biliary excretion of digoxin, but affected little on beta-methyldigoxin clearances. These results suggest that P-gp-mediated drug interactions can easily occur in digoxin, but hardly in beta-methyldigoxin. These findings may give a clue in selecting these digitalis compounds in clinical use, towards escape from P-gp-mediated drug interactions or reduction of interindividual variations.
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PMID:Role of P-glycoprotein in pharmacokinetics and drug interactions of digoxin and beta-methyldigoxin in rats. 1282 Jan 49

The disposition of digoxin and the influence of the organic anion transporting polypeptide (Oatp)2 inhibitor rifampicin and the P-glycoprotein (P-gp) inhibitor quinidine on its hepatic disposition were examined in the isolated perfused rat liver. Livers from groups of rats were perfused in a recirculatory manner after a bolus dose of digoxin (10 microg), a dual substrate for Oatp2 and P-gp as well as CYP3A. Perfusions of digoxin were also examined in groups of rats in the presence of the inhibitors: rifampicin (100 microM) or quinidine (10 microM). In all experiments, perfusate samples were collected for 60 min. Digoxin and its primary metabolite were determined in perfusate and liver by liquid chromatography/mass spectrometry. The area under the curve (AUC) from 0 to 60 min was determined. The AUC +/- S.D. of digoxin was increased from control (3880 +/- 210 nM x min) by rifampicin (5200 +/- 240 nM x min; p < 0.01) and decreased by quinidine (3220 +/- 340 nM x min; P < 0.05). It is concluded that rifampicin limits the hepatic entrance of digoxin and reduced the hepatic exposure of digoxin to CYP3A by inhibiting the basolateral Oatp2 uptake transport, whereas quinidine increased the hepatic exposure of digoxin to CYP3A by inhibiting the canalicular P-gp transport. These data emphasize the importance of uptake and efflux transporters on hepatic drug metabolism.
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PMID:Ex situ inhibition of hepatic uptake and efflux significantly changes metabolism: hepatic enzyme-transporter interplay. 1463 33

Digoxin is a popular cardiac glycoside with very narrow therapeutic range. Quercetin is an ubiquitous antioxidant flavonoid. Digoxin is a substrate of P-glycoprotein (P-gp), a multi-drug efflux transporter, and quercetin was reported to be a modulator of P-gp. The aim of this study was to investigate the effect of quercetin on the absorption and disposition of digoxin in pigs. Pigs were orally given digoxin (0.02 mg/kg) with and without quercetin in crossover designs. The blood was collected via jugular vein and fluorescence polarization immunoassay was used to determine the serum concentration of digoxin. The pharmacokinetic parameters were calculated using WINNONLIN. The paired Student's t-test was used for statistical comparison. The coadministration of 50 mg/kg quercetin unexpectedly resulted in sudden death of two among three pigs within 30 min after digoxin administration. The coadministration of 40 mg/kg quercetin significantly elevated the Cmax of digoxin by 413% and increased the AUC0-t by 170%. The results indicated that a very serious pharmacokinetic interaction occurred between quercetin and digoxin. The concomitant administration of digoxin and quercetin or quercetin-containing herbs and dietary supplement should be avoided.
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PMID:Lethal quercetin-digoxin interaction in pigs. 1469 3

P-glycoprotein (P-gp) is an ATP-dependent efflux membrane transporter involved in many drug pharmacokinetics in humans. Decreasing its expression could enhance the bioavailability of substrates as digoxin. We have recently found that human recombinant interleukin-2 (rIL2) in vivo decreases P-gp expression in intestine and brain of mice and modifies oral digoxin pharmacokinetics. The aim of the study was to evaluate the involvement of bioavailability in the rIL2 pretreatment effect on digoxin pharmacokinetics by comparing oral and i.v. digoxin pharmacokinetics before and after rIL2 pretreatment (10 microg/kg). We also tried to show the possible effect of a low rIL2 dose (1 microg/kg) pretreatment on oral digoxin pharmacokinetics. First, adult Swiss mice received a single oral or i.v. dose of digoxin (0.03 mg/kg). Two weeks later, the same animals were treated by rIL2 i.p. twice a day (10 microg/kg) for 4 days and received digoxin again at day 5. As well, another group received oral digoxin (0.03 mg/kg) with a 1 microg/kg rIL2 pretreatment. Blood was collected after digoxin administration with and without rIL2 pretreatment. Digoxin pharmacokinetics were described by a one-compartment model. The 10 microg/kg rIL2 pretreatment did not modify i.v. digoxin pharmacokinetics, whereas oral digoxin pharmacokinetics were significantly modified by the 10 microg/kg rIL2 pretreatment and not by the 1 microg/kg rIL2 pretreatment. The decrease of P-gp activity, caused by rIL2 (10 microg/kg), increased digoxin bioavailability. An increase in exposure and intracellular level of drugs is expected from rIL2 pretreatment.
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PMID:Effect of recombinant interleukin-2 pretreatment on oral and intravenous digoxin pharmacokinetics and P-glycoprotein activity in mice. 1474 37

Digoxin, which is one of the most commonly prescribed drugs for the treatment of heart failure, is mainly eliminated from the circulation by the kidney. P-glycoprotein is well characterized as a digoxin pump at the apical membrane of the nephron. However, little is known about the transport mechanism at the basolateral membrane. We have isolated an organic anion transporter (OATP4C1) from human kidney. Human OATP4C1 is the first member of the organic anion transporting polypeptide (OATP) family expressed in human kidney. The isolated cDNA encodes a polypeptide of 724 aa with 12 transmembrane domains. The genomic organization consists of 13 exons located on chromosome 5q21. Its rat counterpart, Oatp4c1, is also isolated from rat kidney. Human OATP4C1 transports cardiac glycosides (digoxin, K(m) = 7.8 microM and ouabain, K(m) = 0.38 microM), thyroid hormone (triiodothyronine, K(m) = 5.9 microM and thyroxine), cAMP, and methotrexate in a sodium-independent manner. Rat Oatp4c1 also transports digoxin (K(m) = 8.0 microM) and triiodothyronine (K(m) = 1.9 microM). Immunohistochemical analysis reveals that rat Oatp4c1 protein is localized at the basolateral membrane of the proximal tubule cell in the kidney. These data suggest that human OATP4C1/rat Oatp4c1 might be a first step of the transport pathway of digoxin and various compounds into urine in the kidney.
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PMID:Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. 1499 4


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