Efflux Transport (efflux + transport)

Distribution by Scientific Domains


Selected Abstracts


Blood,brain barrier efflux transport

JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2003
Pamela L. Golden
Abstract Efflux transport at the blood,brain barrier (BBB) limits the brain tissue exposure to a variety of potential therapeutic agents, including compounds that are relatively lipophilic and would be predicted to permeate the endothelial lining of the brain microvasculature. Recent advances in molecular and cell biology have led to identification of several specific transport systems at the blood,brain interface. Refinement of classical pharmacokinetic experimentation has allowed assessment of the structural specificity of transporters, the impact of efflux transport on brain tissue exposure, and the potential for drug,drug interactions at the level of BBB efflux transport. The objective of this minireview is to summarize efflux transporter characteristics (location, specificity, and potential inhibition) for transport systems identified in the BBB. A variety of experimental approaches available to ascertain or predict the impact of efflux transport on net brain tissue uptake of substrates also are presented. The potential impact of efflux transport on the pharmacodynamics of agents acting in the central nervous system are illustrated. Finally, general issues regarding the role of identifying efflux transport as part of the drug development process are discussed. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1739,1753, 2003 [source]


Uptake/Efflux Transport of Tramadol Enantiomers and O -Desmethyl-Tramadol: Focus on P -Glycoprotein

BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2009
Mouna Kanaan
P -glycoprotein (P -gp) might be of importance in the analgesic and tolerability profile variability of TMD. Our study investigated the involvement of P -gp in the transepithelial transport of (+)-TMD, (,)-TMD and M1, using a Caco-2 cell monolayer model. The bidirectional transport of racemic TMD and M1 (1,100 µM) across the monolayers was investigated at two pH conditions (pH 6.8/7.4 and 7.4/7.4) in the presence and absence of P -gp inhibitor cyclosporine A (10 µM) and assessed with the more potent and specific P -gp inhibitor GF120918 (4 µM). Analytical quantification was performed by liquid chromatography coupled to the fluorescence detector. A net secretion of (+)-TMD, (,)-TMD and M1 was observed when a pH gradient was applied (TR: Papp(B , A)/Papp(A , B): 1.8,2.7; P < 0.05). However, the bidirectional transport of all compounds was equal in the non-gradient system. In the presence of P -gp inhibitors, a slight but significant increase of secretory flux was observed (up to 26%; P < 0.05) at both pH conditions. In conclusion, (+)-TMD, (,)-TMD and M1 are not P -gp substrates. However, proton-based efflux pumps may be involved in limiting the gastrointestinal absorption of TMD enantiomers as well as enhancing TMD enantiomers and M1 renal excretion. A possible involvement of uptake carriers in the transepithelial transport of TMD enantiomers and M1 is suggested. [source]


Do multidrug resistance-associated protein-1 and -2 play any role in the elimination of estradiol-17,-glucuronide and 2,4-dinitrophenyl- S -glutathione across the blood,cerebrospinal fluid barrier?

JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2004
Young-Joo Lee
Abstract The purpose of this study was to examine the role of multidrug resistance-associated protein-1 and -2 (Mrp1 and Mrp2) in the efflux transport of organic anions across the blood,cerebrospinal fluid (CSF) barrier. The CSF concentration of estradiol-17,-glucuronide (E217,G) and 2,4-dinitrophenyl- S -glutathione (DNP-SG) in the CSF after intracerebroventricular and intravenous injection were compared between wild-type and Mrp1 gene knockout mice. There was no significant difference in the apparent CSF elimination rate constants of E217,G (0.158 and 0.145 min,1) and DNP-SG (0.116 and 0.0779 min,1) between wild-type and Mrp1 knockout mice, respectively. After intravenous administration of E217,G, its brain-to-serum and CSF-to-serum concentration ratios in Mrp1 knockout mice were not significantly different from those in the wild-type. Results from in vivo and in vitro studies using Eisai hyperbilirubinemic rats, in which Mrp2 is hereditarily deficient, were similar to those using normal rats. Quantitative polymerase chain reaction (PCR) showed that the expression level of Mrp4 and Mrp5 was several times higher than that of Mrp1, whereas the expression levels of Mrp2, Mrp3, and Mrp6 were negligible or low. Therefore, Mrp4 and Mrp5 may contribute to the efflux transport of E217,G and DNP- SG from the CSF. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:99,107, 2004 [source]


Blood,brain barrier efflux transport

JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2003
Pamela L. Golden
Abstract Efflux transport at the blood,brain barrier (BBB) limits the brain tissue exposure to a variety of potential therapeutic agents, including compounds that are relatively lipophilic and would be predicted to permeate the endothelial lining of the brain microvasculature. Recent advances in molecular and cell biology have led to identification of several specific transport systems at the blood,brain interface. Refinement of classical pharmacokinetic experimentation has allowed assessment of the structural specificity of transporters, the impact of efflux transport on brain tissue exposure, and the potential for drug,drug interactions at the level of BBB efflux transport. The objective of this minireview is to summarize efflux transporter characteristics (location, specificity, and potential inhibition) for transport systems identified in the BBB. A variety of experimental approaches available to ascertain or predict the impact of efflux transport on net brain tissue uptake of substrates also are presented. The potential impact of efflux transport on the pharmacodynamics of agents acting in the central nervous system are illustrated. Finally, general issues regarding the role of identifying efflux transport as part of the drug development process are discussed. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1739,1753, 2003 [source]


Role of P-glycoprotein in pharmacokinetics and drug interactions of digoxin and ,-methyldigoxin in rats

JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2003
Sachiyo Funakoshi
Abstract Digoxin and ,-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 (CLtotal) as well as biliary and urinary excretions after intravenous administration. Both the intestinal efflux transport and absorption of ,-methyldigoxin were approximately 1.5-fold greater than those of digoxin, probably due to its higher lipophilicity. Addition of verapamil (300 ,M) significantly decreased the intestinal efflux transport and increased the intestinal absorption of digoxin. In contrast, the influence of verapamil on ,-methyldigoxin was small. Intravenous cyclosporin A (30 mg/kg) significantly decreased in vivo CLtotal and biliary excretion of digoxin, but affected little on ,-methyldigoxin clearances. These results suggest that P-gp-mediated drug interactions can easily occur in digoxin, but hardly in ,-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. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1455,1463, 2003 [source]


Mechanism of decrease of oral bioavailability of cyclosporin A during immunotherapy upon coadministration of amphotericin B

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2008
Junko Ishizaki
Abstract The trough level of blood concentration of cyclosporin A (CyA) in a patient receiving immunotherapy was observed to decrease following coadministration of amphotericin B (AMB). This clinical observation was confirmed experimentally in Wistar rats intravenously given AMB (1.5 or 3.0,mg/kg) or saline (control) for 4 days, followed by CyA (10,mg/kg). The blood concentration of CyA after i.v. or p.o. administration in both AMB groups was significantly decreased compared with the control. The oral bioavailability of CyA after 1.5 or 3.0,mg/kg AMB treatment was decreased to 67% or 46%, respectively, of that of the control group. AMB treatment increased the expression levels of mdr1a and mdr1b mRNAs in the duodenum to about three times the control, and expression of CYP3A2 mRNA in the liver was increased to about twice the control. The P-gp and CYP3A2 proteins were increased significantly. These findings suggest that the oral bioavailability of CyA is reduced as a result of both increased efflux transport via P-glycoprotein in the duodenum and an increased first-pass effect of CYP3A2-mediated hepatic metabolic activity, induced by AMB. It is suggested that careful monitoring of CyA levels is necessary in the event of AMB administration to patients receiving immunotherapy with CyA. Copyright © 2008 John Wiley & Sons, Ltd. [source]


Apparent active transport of MDMA is not mediated by P-glycoprotein: a comparison with MDCK and Caco-2 monolayers

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2006
Kirk M. Bertelsen
Abstract Amphetamines and their methylenedioxy derivatives generically display similar behavioral, physiologic and toxic effects. Inconsistent pharmacokinetic and toxicity data for methylenedioxymethamphetamine (MDMA) may suggest that active drug transporters are interacting with these compounds, and thus altering drug absorption and tissue distribution. In vitro models of CNS accumulation and intestinal drug transport were used to assess efflux transport of MDMA. Madin-Darby kidney cell epithelial (MDCK) monolayers displayed a 4-fold increase in accumulation in the basolateral to apical orientation relative to the apical to basolateral orientation, although no differential accumulation was noted between MDCK-WT and MDCK-MDR1 monolayers. Caco-2 monolayers demonstrated an approximate 2-fold increase in accumulation of MDMA. Exposure of various inhibitors of active drug transporters demonstrated mixed results; ritonavir, progesterone and indomethacin produced an approximately 50% reduction of MDMA transport, while verapamil, MK-571 and probenecid had no effect. Based on these data, it is concluded that MDMA efflux is mediated via the activity of a transporter distinct from P-glycoprotein. The possible inhibitory effects of amphetamines on rhodamine-123 transport were also assessed. MDMA, methylenedioxyamphetamine, amphetamine and methamphetamine, at physiologically relevant concentrations, did not significantly alter the transport of rhodamine-123 in Caco-2 monolayers or the LS180 cell line, suggesting that these compounds do not alter the function of P-glycoprotein. Copyright © 2006 John Wiley & Sons, Ltd. [source]