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)

Iodide efflux, an index of anion permeability, has been monitored in cultured rat brain endothelial cells. Following hypotonicity-induced swelling, large, rapid increases in permeability occur, the extent of these increases depending on the degree of hypotonicity. Such large responses are not observed with rat aortic endothelial cells. Results of anion substitution experiments suggest that iodide efflux is via a chloride channel rather than an exchanger. The efflux increase is blocked by NPPB (100 microM) but not by DIDS or DPC at 100 microM. It is dependent on intracellular ATP but unaffected by removal of external calcium. Increasing internal calcium using A23187 does not produce a change in efflux, but depletion of calcium reduces or eliminates the response to hypotonicity. The response is reduced by pimozide (2-50 microM) that inhibits the actions of calmodulin and by pBPB (10 microM) that affects phospholipase A2 activity. It is eliminated by 5-lipoxygenase inhibitors (L-656,224 and ETH615, 10 microM) but is unaffected by cyclo-oxygenase inhibitors (indomethacin and piroxicam, 1-100 microM). It is blocked by some modulators of P-glycoprotein activity, e.g., verapamil (100 microM), tamoxifen (50 microM), and progesterone (100 microM) but not by others, e,g., forskolin (40 microM), dideoxyforskolin (40 microM), quinidine (100 microM) and cyclosporin A (10 microM).
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PMID:Hypotonicity-induced changes in anion permeability of cultured rat brain endothelial cells. 910 87

N-[(3-fluorophenyl)methyl]glycyl-N-[3-[((3-aminophenyl)sulfonyl)- 2-(aminophenyl)amino]-(1S,2S)-2-hydroxy-1-(phenylmethyl)propyl]- 3-methyl-L-valinamide (DPC 681, DPC(1)) on oral coadministration with ritonavir (RTV) in rats caused a significant increase in systemic exposure to DPC. Following a single oral dose of [(14)C]DPC with and without RTV pretreatment in rats, and subsequent analysis of whole-body sections, prepared at 1 and 7 or 8 h postdose, using whole-body autoradiography showed an increase in radioactivity in tissues (e.g., brain, and testes) upon coadministration. The distribution of radioactivity in the brain parenchyma and ventricles was different, such that the concentration of radioactivity was greater in cerebrospinal fluid (CSF) than in central nervous system. Thus, the use of CSF concentration of the total radioactivity as a surrogate for brain penetration would result in an overestimation. DPC was determined to be metabolized prominently by rCYP3A4. The increased tissue exposure to DPC in rats could largely be attributed to inhibition of CYP3A1/2 by RTV. DPC was also a good substrate for P-glycoprotein (Pgp), with K(m) of 4 microM and V(max) of 13 pmol/min. The Pgp-mediated transport of DPC across Caco-2 cells was readily saturated at >or=10 microM and was inhibited significantly by RTV at 5 to 10 microM. The data above and the reported RTV concentrations suggested that both the Pgp and CYP3A4 inhibition by RTV may play a significant role in enhancing the systemic and tissue exposure to DPC in humans.
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PMID:Interaction of ritonavir on tissue distribution of a [(14)c]L-valinamide, a potent human immunodeficiency virus-1 protease inhibitor, in rats using quantitative whole-body autoradiography. 1238 20

The role of the intestine in the elimination of (2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide (DPC 333), a potent inhibitor of tissue necrosis factor alpha-converting enzyme, was investigated in mice and rats in vivo and in vitro. In Madine-Darby canine kidney cells stably transfected with P-glycoprotein (P-gp) and DPC 333, the transport from B-->A reservoirs exceeded the transport from A-->B by approximately 7-fold. In Caco-2 monolayers and isolated rat ileal mucosa, DPC 333 was transported from basolateral to apical reservoirs in a concentration-dependent, saturable manner, and transport was blocked by N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), confirming the contribution of P-gp/breast cancer resistance protein in B-->A efflux of DPC 333. In quantitative whole body autoradiography studies with [(14)C]DPC 333 in mice and rats, radioactivity was distributed throughout the small intestine in both species. In GF120918-pretreated bile duct-cannulated rats, radioactivity in feces was reduced 60%. Using the in situ perfused rat intestine model, approximately 20% of an i.v. dose of [(14)C]DPC 333 was measured in the intestinal lumen within 3 h postdose, 12% as parent. Kinetic analysis of data suggested that excreted DPC 333 may be further metabolized in the gut. Intestinal clearance was 0.2 to 0.35 l/h/kg. The above data suggest that in the rodent the intestine serves as an organ of DPC 333 excretion, mediated in part by the transporter P-gp.
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PMID:Role of P-glycoprotein and the intestine in the excretion of DPC 333 [(2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] in rodents. 1834 85