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)

Topotecan (TPT, 9-dimethylaminomethyl-10-hydroxycamptothecin) is the first topoisomerase I-directed cytotoxic agent to enter clinical trials in the United States in two decades. The effect of P-glycoprotein (Pgp) overexpression on TPT cytotoxicity was examined in CHRC5 (colchicine-resistant) and AuxB1 (parental) Chinese hamster ovary cells. Examination of the IC50 values observed in colony-forming assays revealed that the CHRC5 cells were 15-fold (SD, +/- 3; n = 3) resistant to TPT after a 1-h exposure and 3.2-fold (SD, +/- 1.4; n = 4) resistant in continuous exposure experiments. Band depletion immunoblotting revealed that 4-fold higher concentrations of extracellular TPT were required to induce the formation of topo I-DNA complexes in CHRC5 cells as compared to AuxB1 cells. To assess the role of Pgp in this resistance, drug accumulation and cytotoxicity assays were repeated in the absence and presence of quinidine. Addition of quinidine enhanced TPT accumulation (measured by high-performance liquid chromatography) and diminished the IC50 for TPT to a greater extent in CHRC5 cells than in AuxB1 cells. To examine whether similar effects could be detected in Pgp-expressing human cells, MCF-7/Adriar breast cancer cells and KG1a human acute myelogenous leukemia cells were examined. Quinidine or verapamil enhanced TPT accumulation in both of these cell lines but had no effect in parental MCF-7 cells or a variety of human leukemia cell lines that do not overexpress Pgp. Cytotoxicity measurements performed by counting the number of surviving cells (MCF-7/Adriar) or employing a modified, highly stable tetrazolium dye reduction assay (leukemia cell lines) revealed that quinidine diminished the IC50 for TPT in the Pgp-overexpressing cell lines but not in the control lines. These results suggest that Pgp overexpression diminishes TPT accumulation and TPT cytotoxicity in hamster and human cells. It should be stressed, however, that these effects were substantially smaller than the effects of Pgp overexpression on the accumulation and cytotoxicity of the anthracycline daunorubicin and the epipodophyllotoxin etoposide in the same cell lines.
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PMID:Effect of P-glycoprotein expression on the accumulation and cytotoxicity of topotecan (SK&F 104864), a new camptothecin analogue. 134 48

This article represents the first evidence that the renal secretion of the commonly used drug, digoxin, is mediated by P-glycoprotein. In this study, it was demonstrated that digoxin is a substrate of P-glycoprotein, and the mechanism of a clinically important drug interaction, such as digoxin-quinidine, was elucidated. Human P-glycoprotein was expressed on the apical membrane of the porcine kidney epithelial cell line, LLC-PK1 by transfecting with human MDR1 cDNA. The expression and function of P-glycoprotein were confirmed by Southern and Western blotting, RNase protection assay, immunostaining and transporting activity for vinblastine. The transepithelial transport of [3H]digoxin was measured across the cell monolayers grown on microporous polycarbonate membrane filters. The transfectant cells exhibited markedly greater basal-to-apical transport and less apical-to-basal transport than the host cells, and the former was 8-fold greater than the latter. The augmented transepithelial transport resulted from the increased efflux from cells to apical side. This oriented transport was inhibited by the presence of 20 microM vinblastine, quinidine or verapamil. The rate of efflux to the apical side was 2-fold greater than that to the basal side. Quinidine inhibited the efflux to the apical side but did not affect transport into the basal side. These findings demonstrate that digoxin is transported by human P-glycoprotein, which is a previously undiscovered drug transport system in the kidney other than organic cation and anion transport systems, and suggest a molecular mechanism for the renal tubular secretion of digoxin as well as clinically important digoxin-quinidine interaction via P-glycoprotein.
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PMID:Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). 135 20

P-glycoprotein (Pgp) actively pumps a number of antineoplastic drugs, such as etoposide, out of cancer cells and causes multidrug resistance. Pgp is also expressed at the brush-border membrane of the small intestine under normal physiological conditions. We hypothesized that inhibition of intestinal Pgp might decrease the efflux of etoposide from the blood into the intestinal lumen, thereby, increasing the bioavailability of etoposide. The absorption of etoposide was studied using everted gut sacs prepared from rat jejunum and ileum. The addition of C219, a monoclonal antibody of Pgp, at 100 ng/ml or of 0.2 M 5'-adenylylimidodiphosphate, a nonhydrolyzable adenosine triphosphate (ATP) analog, increased the absorption of etoposide. Quinidine, an antiarrythmic agent, has been demonstrated to circumvent multidrug resistance in cell lines, possibly by interfering with Pgp function. Adding quinidine at 1 mg/ml to the everted gut sac increased the absorption of etoposide. In vivo absorption of etoposide was also studied by intraluminal perfusion of the drug in the small intestine of anesthetized rats. Intravenous infusion of quinidine at either 1 or 2 mg/h increased the serum level of etoposide in a dose-dependent manner. Intravenous infusion of etoposide at 0.2 mg/h resulted in luminal exsorption of the drug in the small intestine. The intestinal clearance of etoposide was 41.7 +/- 7.2 ml kg-1, which decreased to 18.4 +/- 3.9 ml kg-1 with the infusion of quinidine at 1 mg/h. The present data confirm that intestinal Pgp mediates the efflux of etoposide and that the use of Pgp-inhibiting agents such as quinidine may increase the bioavailability of etoposide.
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PMID:Inhibition of intestinal P-glycoprotein and effects on etoposide absorption. 785 Sep 26

The mechanism for renal tubular secretion of digoxin as well as its interaction with quinidine or verapamil were investigated using the isolated perfused rat kidney. [3H]Digoxin was instantaneously administered into the renal artery together with [14C]inulin and Evans blue-albumin, and renal venous and urinary outflow curves were measured. The ratio of fractional excretion to filtration fraction for digoxin was 2.40 +/- 0.40, indicating involvement of tubular secretion. Quinidine and verapamil decreased the ratio of fractional excretion to filtration fraction in a concentration-dependent manner, and this inhibition was indicated to occur at transport from cells to lumen across luminal membranes. Neither tetraethylammonium nor p-aminohippurate affected the renal handling of digoxin. Because ouabain and digitoxose showed no influence on the value of fractional excretion to filtration fractions, Na+,K(+)-ATPase is not involved in the tubular secretion of digoxin. A metabolic inhibitor, 2,4-dinitrophenol, markedly inhibited digoxin secretion. Agents that bind to P-glycoprotein, such as vinblastine, daunorubicin and reserpine, markedly inhibited the secretion of digoxin. Recently, we have found that digoxin is a substrate transported by P-glycoprotein. The findings obtained here support the hypothesis that digoxin is secreted by P-glycoprotein located on the luminal membrane of renal tubular epithelial cells, and that clinically important interactions with quinidine and verapamil are caused by the inhibition of P-glycoprotein.
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PMID:Role of P-glycoprotein in renal tubular secretion of digoxin in the isolated perfused rat kidney. 810 98

Daunomycin, an anti-neoplastic agent, is known to be sequestered by acidic organelles in normal and multidrug-resistant cells [Willingham, M.C., Cornwell, M.M., Cardarelli, C.O., Gottesman, M.M., & Pastan, I. (1986) Cancer Res. 46, 5941-5946]. We studied the mechanism of accumulation of daunomycin into acidic organelles using chromaffin granule vesicles and proteoliposomes reconstituted with purified F-type H(+)-ATPase as model systems. Radiolabeled daunomycin was taken up by chromaffin vesicles upon addition of ATP. Its ATP-dependent uptake was stimulated about 1.4- to 1.8-fold by valinomycin plus K+, but was inhibited by ammonium chloride (10 mM) and nigericin plus K+. Quinidine (5 microM), verapamil (5 microM), or vanadate (0.5 mM), inhibitors of P-glycoprotein, had no effect on its uptake. Daunomycin was also taken up by liposomes reconstituted with F-type H(+)-ATPase. Furthermore, doxorubicin and vinblastine were taken up by these vesicles, whereas colchicine and rhodamine 123 were not. The accumulations of daunomycin and doxorubicin in acidic organelles of cultured cells were decreased by inhibiting vacuolar ATPase by addition of bafilomycin A1 or concanamycin A, or by increasing the internal pH by addition of nigericin. Melittin and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide dissipated the delta pH and inhibited accumulation of daunomycin in the membrane vesicles and acidic organelles in cultured cells. These results indicate that the delta pH established by vacuolar-type ATPase drives the uptake of daunomycin, doxorubicin or vinblastine into acidic organelles, and that no specific transporters are involved in their uptakes.
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PMID:ATP-dependent uptake of anti-neoplastic agents by acidic organelles. 820 70

Pesticides have been shown to interact with the multidrug resistance protein associated with cancer chemotherapy, P-glycoprotein (P-gp). P-gp, therefore, has also been implicated in the development of pesticide resistance. The purpose of this study was to characterize the effect P-gp has on the accumulation of the carbamate pesticide, thiodicarb. For these studies, resistant tobacco budworm larvae, expressing four times the P-gp as susceptible larvae, were pretreated with the P-gp inhibitor, quinidine, and challenged topically with thiodicarb. Quinidine enhanced thiodicarb toxicity in a dose-dependent manner, with mortality in the presence of P-gp inhibition increased up to 33%. Quinidine treatment increased [14C]thiodicarb accumulation 2- to 3-fold as compared to thiodicarb treatment alone. This study suggests that P-gp contributes to quinidine synergism of thiodicarb toxicity and suggests that P-gp may be involved in cuticular resistance to pesticides.
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PMID:P-glycoprotein involvement in cuticular penetration of [14C]thiodicarb in resistant tobacco budworms. 864 24

Since pesticides have been shown to interact with P-glycoprotein (P-gp), the purpose of this study was to examine the possible role of P-gp in pesticide resistance in the tobacco budworm (Heliothis virescens). Using three P-gp antibodies, P-gp expression in various resistant populations of tobacco budworms was found to be 2-6-times that of the susceptible larvae. Tobacco budworm P-gp was glycosylated and localized primarily in the cuticle and fat body with little expression in the mid gut. To determine the role of P-gp in pesticide resistance, resistant tobacco budworm larvae were treated with a P-gp inhibitor, quinidine, and challenged with various doses of thiodicarb. Inhibition of P-gp decreased the LD50 for thiodicarb by a factor of 12.5. Quinidine treatment did not result in a significant inhibition of the P-450 system nor did it alter the feeding of the larvae, suggesting the potential involvement of P-gp in pesticide resistance. An age-dependent increase in P-gp expression was detected in resistant larvae as compared to control, susceptible larvae. This correlates with the reported age-dependent increase in resistance and is further evidence supporting the role of P-gp in the development of pesticide resistance.
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PMID:Tobacco budworm P-glycoprotein: biochemical characterization and its involvement in pesticide resistance. 889 77

Recent studies suggest that P-glycoprotein located on the blood-brain barrier restricts the brain uptake of its substrates. We examined the role of P-glycoprotein on the restricted entry of quinidine to the brain. Quinidine is a well known inhibitor of P-glycoprotein, although it is not yet clarified whether quinidine is the substrate for P-glycoprotein. Kinetic analysis of the uptake of quinidine into the rat brain after intravenous bolus administration revealed that the net uptake clearance is 25.5 microl/min/g brain. Intravenous administration of SDZ PSC 833, a multidrug resistance modifier, enhanced the net uptake clearance of quinidine by 15.7-fold. In contrast, no enhancement by SDZ PSC 833 was observed for the brain uptake of mannitol, a marker for the passive diffusion across the blood-brain barrier. The elimination of [3H] quinidine from the rat brain after microinjection into the cerebral cortex was inhibited by preadministered unlabeled quinidine and verapamil. In addition, the brain-to-plasma concentration ratio of quinidine at 10 min after intravenous administration was 27. 6-fold higher in mdr1a knock-out mice than in control mice. These results suggest that P-glycoprotein mediates the efflux of quinidine across the blood-brain barrier, resulting in its restricted entry to the brain.
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PMID:P-Glycoprotein mediates the efflux of quinidine across the blood-brain barrier. 935 72

The intestinal transport of quinidine was characterized in rat small intestine, using the Ussing-type chamber under short-circuited conditions. In the short-circuited condition, quinidine transport was predominantly secretory and the transport rate in jejunum was 3.5 times larger in the secretory direction than that in the absorptive direction. The secretion of quinidine was found to be dependent upon its concentration and to be via a carrier-mediated system in both jejunum and ileum. Although the kinetic characteristic of the carrier-mediated secretion of quinidine was very similar in jejunum and ileum, its contribution was much greater in jejunum because of a higher passive diffusion component in ileum. The secretion of quinidine, well-known as an inhibitor of P-glycoprotein, was inhibited significantly and its absorption was enhanced significantly by several substrates of P-glycoprotein including verapamil, diltiazem, and digitoxin in jejunum. These phenomena were also observed by the addition of 2,4-dinitrophenol. Furthermore, the voltage-clamp studies indicated that the inhibition of quinidine secretion occurred in the transcellular pathway. On the other hand, neither tetraethylammonium nor p-aminohippuric acid affected the transport of quinidine. Quinidine was also recognized to inhibit the secretion and to promote the absorption of substrates of P-glycoprotein, chlorpromazine, and verapamil. These results strongly suggest that quinidine is not only an inhibitor but also a substrate of P-glycoprotein and that the P-glycoprotein-mediated secretory flux acts as a barrier to quinidine absorption in the small intestine, especially jejunum.
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PMID:Role of P-glycoprotein as a secretory mechanism in quinidine absorption from rat small intestine. 952 81

The prediction error in the Bayesian analysis program for digoxin was evaluated in Japanese patients, and factors influencing the accuracy were investigated. Serum concentrations of digoxin were monitored two times and were compared with the predicted values obtained by using the Bayesian analysis program. The prediction error at the first time was 43.1%. Although this estimation error was reasonably restored at the second time of monitoring, the prediction error remained at 26.6%. These data suggested that unknown factors not included in the program affected the serum concentration of digoxin. Retrospective research of the digoxin serum concentrations in the patients suggested the coadministration of the drugs, which were the P-glycoprotein modulators, as well as the unexpected alteration of the serum creatinine, were the important factors influencing the prediction of the drug serum concentrations. We next examined the inhibitory effect of quinidine, verapamil and spironolactone on the transcellular transport of digoxin by using human P-glycoprotein overexpressing LLC-GA5-COL150 cells. Quinidine, verapamil and spironolactone could inhibit the transcellular transport of digoxin by 50%. In addition, the reduction of the renal clearance by 50%, which could possibly be caused by this inhibition, led to the increase of 36% in the steady state through concentrations of digoxin in the physiological pharmacokinetic model. In conclusion, the prediction of long-term serum concentration-time profiles of digoxin, based on the Bayesian analysis, will be disturbed by the coadministration of the P-glycoprotein modulators and the unexpected alteration of the serum creatinine.
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PMID:Factors influencing the prediction of steady state concentrations of digoxin. 1130 3


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