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Amyloid-β (Aβ) is the major component of the insoluble amyloid plaques that accumulate intracerebrally in patients with Alzheimer’s disease (AD). It has been suggested that MDR1-P-glycoprotein (ABCB1, P-gp) plays a substantial role in the elimination of Aβ from the brain. In the present study, MDR1-transfected LLC cells growing in a polarized cell layer were used to characterize the interaction of Aβ1-40/1-42 with P-gp. In this system, P-gp-mediated transport can be followed by the efflux of the fluorescent dye rhodamine-123, or of Aβ itself from the cells into the apical extracellular space. Aβ significantly decreased the apical efflux of rhodamine-123, and the transcellular transport of Aβ1-40 and Aβ1-42 into the apical chamber could be demonstrated using both ELISA and fluorescence (FITC)-labeled peptides. This transport was inhibited by a P-gp modulator. Furthermore, ATP-dependent, P-gp-mediated transport of the fluorescence-labeled peptides could be demonstrated in isolated, inside-out membrane vesicles. Our data support the concept that P-gp is important for the clearance of Aβ from brain, and thus may represent a target protein for the prevention and/or treatment of neurodegenerative disorders such as AD. [ABSTRACT FROM AUTHOR]

Background and Aims: Ezetimibe is an inhibitor of the cholesterol uptake transporter Niemann-Pick C1-like protein (NPC1L1). Target concentrations can be influenced by intestinal uridine diphosphate–glucuronosyltransferases (UGTs) and the efflux transporters P-glycoprotein (P-gp) (ABCB1) and multidrug resistance associated protein 2 (MRP2) (ABCC2). This study evaluates the contribution of these factors to the disposition and cholesterol-lowering effect of ezetimibe before and after induction of UGT1A1, P-gp, and MRP2 with rifampin (INN, rifampicin).Methods: Serum concentrations of ezetimibe, as well as its glucuronide, and the plant sterols campesterol and sitosterol (surrogate for cholesterol absorption) were studied in 12 healthy subjects before and after rifampin comedication. In parallel, duodenal expression of UGT1A1, P-gp, MRP2, and NPC1L1 was quantified by use of real-time reverse transcriptase–polymerase chain reaction and quantitative immunohistochemical evaluation. The affinity of ezetimibe and its glucuronide to P-gp and MRP2 was assessed in P-gp– overexpressing Madin-Darby canine kidney II cells and P-gp–containing or MRP2-containing inside-out vesicles.Results: Up-regulation of intestinal P-gp, MRP2, and UGT1A1 (but not of NPC1L1) by rifampin was associated with markedly decreased areas under the curve of ezetimibe and its glucuronide (116 ± 78.1 ng·h/mL versus 49.9 ± 31.0 ng·h/mL and 635 ± 302 ng·h/mL versus 225 ± 86.4 ng·h/mL, respectively; both P = .002) and increased intestinal clearances (2400 ± 1560 mL/min versus 5500 ± 4610 mL/min [P = .003] and 76.6 ± 113 mL/min versus 316 ± 457 mL/min [P = .010], respectively) and nearly abolished sterol-lowering effects. Intestinal expression of UGT1A1, ABCB1, and ABCC2 was inversely correlated with the effects of ezetimibe on plant sterol serum concentrations. Parallel in vitro studies confirmed that ezetimibe glucuronide is a high-affinity substrate of MRP2 and has a low affinity to P-gp whereas ezetimibe interacts with P-gp and MRP2.Conclusions: The disposition and sterol-lowering effects of ezetimibe are modified by metabolic degradation of the drug via intestinal UGT1A1 and either intestinal or hepatic secretion (or both) via P-gp and MRP2.Clinical Pharmacology & Therapeutics (2006) 79, 196–196; doi: 10.1016/j.clpt.2005.11.004 [ABSTRACT FROM AUTHOR]

ATP-binding cassette(ABC) transporters comprise one of the largest membrane bound protein families. They are involved in transport of numerous compounds. These proteins transport substrates against a concentration gradient with ATP hydrolysis as a driving force across the membrane. Mammalian ABC proteins have important physiological, pharmacological and toxicological functions including the transport of lipids, bile salts, drugs, toxic and environmental agents. The efflux pumps serve both as natural defense mechanisms and influence the bioavailability and disposition of drugs. In general terms, the transporters remove xenobiotics from the cellular environment. For example, in cancer cells, over expression of these molecules may confer to multidrug resistance against cytostatic drugs. In addition, based on diverse structural characteristics and a broad substrate specifity, ABC transport proteins alter the intracellular concentration of a variety of therapeutically used compounds and toxicologically relevant agents. We review the function of the human multidrug resistance protein MDR1,(P-glycoprotein, ABCB1) and the multidrug resistance protein MRP2(ABCC2). We focus on four topics namely 1) structure and physiological functions of these transporters, 2) substrates e.g., drugs, xenotoxins, and environmental toxicants including their conjugates, 3) drug–drug interactions, and the role of chemosensitizers which may be able to reverse drug resistance, and 4) pharmacologically and toxicologically relevant genetic polymorphisms in transport proteins and their clinical implications. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the association of non-response to antiepileptic pharmacotherapy with the frequency of variant alleles in the drug transporter genes ABCB1 and ABCC2 or in the CYP2C locus in young patients with epilepsy and an independent cohort of adults with drug-refractory epilepsy.A total of 221 pediatric or adolescent Caucasian patients with epilepsy (105 females; age: 14.5±6.54 years) were genotyped for nine putatively functionally relevant ABCB1, ABCC2, CYP2C8, CYP2C9, and CYP2C19 polymorphisms. In addition, 70 adult patients (35 females, age: 41.9±11.5 years) with drug-refractory epilepsy who had earlier undergone neurosurgical therapy were genotyped and partly (n = 22) investigated for hippocampal ABCB1 and ABCC2 mRNA expression. Finally, 242 healthy volunteers (167 females, age: 27.0±6.77 years) from the same region were included as controls.The young cohort consisted of 103 (46.6%) responders and 118 (53.4%) non-responders to the first-line anticonvulsant. Carriers of the putatively low-expression ABCC2 -24T variant were significantly overrepresented among non-responders [odds ratio (OR) 2.15 (1.16-3.99); P = 0.016)]. This overrepresentation was confirmed by comparing young responders with adult drug-refractory patients [OR 3.36 (1.71-6.59); P<0.001]. Conversely, ABCB1 genotype distribution did not significantly differ between young responders and non-responders or adult drug-refractory patients. Excluding patients with febrile convulsions, heterozygous CYP2C8∗4 [OR 0.35 (0.13-0.95); P = 0.038] and CYP2C9∗3 [OR 0.34 (0.14-0.81); P = 0.015] variant allele carriers were underrepresented among non-responders. ABCC2 -24C>T genotype did not affect hippocampal ABCC2 expression, but was associated with increased ABCB1 expression (P = 0.034).These data suggest a higher risk of antiepileptic drug failure in ABCC2 -24T allele carriers possibly because of compensatory upregulation of ABCB1. [ABSTRACT FROM AUTHOR]

Discusses issues related to a study on the role of intestinal P-glycoprotein (P-gp) in the interaction of digoxin and rifampin. Relationship between intestinal P-gp and digoxin bioavailability; Concern regarding the calculation of oral digoxin bioavailability AUC.