Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell culture-based blood-brain barrier (BBB) models are useful tools for screening of CNS drug candidates. Cell sources for BBB models include primary brain endothelial cells or immortalized brain endothelial cell lines. Despite their well-known differences, epithelial cell lines are also used as surrogate models for testing neuropharmaceuticals. The aim of the present study was to compare the expression of selected BBB related genes including tight junction proteins, solute carriers (SLC), ABC transporters, metabolic enzymes and to describe the paracellular properties of nine different culture models. To establish a primary BBB model rat brain capillary endothelial cells were co-cultured with rat pericytes and astrocytes (EPA). As other BBB and surrogate models four brain endothelial cells lines, rat GP8 and RBE4 cells, and human hCMEC/D3 cells with or without lithium treatment (D3 and D3L), and four epithelial cell lines, native human intestinal Caco-2 and high P-glycoprotein expressing vinblastine-selected VB-Caco-2 cells, native MDCK and MDR1 transfected MDCK canine kidney cells were used. To test transporter functionality, the permeability of 12 molecules, glucopyranose, valproate, baclofen, gabapentin, probenecid, salicylate, rosuvastatin, pravastatin, atorvastatin, tacrine, donepezil, was also measured in the EPA and epithelial models. Among the junctional protein genes, the expression level of occludin was high in all models except the GP8 and RBE4 cells, and each model expressed a unique claudin pattern. Major BBB efflux (P-glycoprotein or ABCB1) and influx transporters (GLUT-1, LAT-1) were present in all models at mRNA levels. The transcript of BCRP (ABCG2) was not expressed in MDCK, GP8 and RBE4 cells. The absence of gene expression of important BBB efflux and influx transporters BCRP, MRP6, -9, MCT6, -8, PHT2, OATPs in one or both types of epithelial models suggests that Caco-2 or MDCK models are not suitable to test drug candidates which are substrates of these transporters. Brain endothelial cell lines GP8, RBE4, D3 and D3L did not form a restrictive paracellular barrier necessary for screening small molecular weight pharmacons. Therefore, among the tested culture models, the primary cell-based EPA model is suitable for the functional analysis of the BBB.
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PMID:Comparison of a Rat Primary Cell-Based Blood-Brain Barrier Model With Epithelial and Brain Endothelial Cell Lines: Gene Expression and Drug Transport. 2987 78

The pharmacokinetics of a drug is dependent upon the coordinate work of influx transporters, enzymes and efflux transporters (i.e., transporter-enzyme interplay). The transporter-enzyme interplay may occur in liver, kidney and intestine. The influx transporters involving drug transport are organic anion transporting polypeptides (OATPs), peptide transporters (PepTs), organic anion transporters (OATs), monocarboxylate transporters (MCTs) and organic cation transporters (OCTs). The efflux transporters are P-glycoprotein (P-gp), multidrug/toxin extrusions (MATEs), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). The enzymes related to drug metabolism are mainly cytochrome P450 enzymes (CYP450s) and UDP-glucuronosyltransferases (UGTs). Accumulating evidence has demonstrated that diabetes alters the expression and functions of CYP450s and transporters in a different manner, disordering the transporter-enzyme interplay, in turn affecting the pharmacokinetics of some drugs. We aimed to focus on (1) the imbalance of transporter-CYP450 interplay in the liver, intestine and kidney due to altered expressions of influx transporters (OATPs, OCTs, OATs, PepTs and MCT6), efflux transporters (P-gp, BCRP and MRP2) and CYP450s (CYP3As, CYP1A2, CYP2E1 and CYP2Cs) under diabetic status; (2) the net contributions of these alterations in the expression and functions of transporters and CYP450s to drug disposition, therapeutic efficacy and drug toxicity; (3) application of a physiologically-based pharmacokinetic model in transporter-enzyme interplay.
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PMID:Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance. 3229 May 19