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)

We previously used killifish proximal tubules, fluorescent substrates, and confocal microscopy to demonstrate that transport mediated by the multidrug resistance protein (Mrp2) and by P-glycoprotein was reduced by nanomolar concentrations of endothelin-1 (ET), acting through a basolateral B-type ET receptor and protein kinase C (PKC). Here we show that representatives of two classes of nephrotoxicants decrease transport by activating the endothelin-PKC signaling pathway. Exposing tubules to radiocontrast agents (iohexol, diatrizoate) or aminoglycoside antibiotics (gentamicin, amikacin) reduced Mrp2-mediated fluorescein methotrexate (FL-MTX) transport from cell to tubular lumen. Pretreating the tubules with an ET(B)-receptor antagonist or with PKC-selective inhibitors abolished these effects. The nephrotoxicants activated signaling by inducing release of ET from the tubules, because adding of an antibody against ET to the medium abolished the effects. Elevating medium Ca(2+) also reduced FL-MTX transport; this reduction was abolished when tubules were pretreated with an ET antibody, an ET(B)-receptor antagonist, PKC-selective inhibitors, or the Ca(2+) channel blocker, nifedipine. None of these drugs by themselves affected FL-MTX transport. Importantly, nifedipine also blocked the ET(B)-receptor/PKC-dependent reduction in FL-MTX transport caused by gentamicin and diatrizoate. These results for two classes of structurally unrelated nephrotoxicants suggest that Ca(2+)-dependent ET release and subsequent action through an autocrine mechanism may be an early response to tubular injury.
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PMID:Nephrotoxicants induce endothelin release and signaling in renal proximal tubules: effect on drug efflux. 1135 3

This review describes the pharmacokinetics of the major drugs used for the treatment of inflammatory bowel disease. This information can be helpful for the selection of a particular agent and offers guidance for effective and well tolerated regimens. The corticosteroids have a short elimination half-life (t1/2beta) of 1.5 to 4 hours, but their biological half-lives are much longer (12 to 36 hours). Most are moderate or high clearance drugs that are hepatically eliminated, primarily by cytochrome P450 (CYP) 3A4-mediated metabolism. Prednisone and budesonide undergo presystemic elimination. Any disease state or comedication affecting CYP3A4 activity should be taken into account when prescribing corticosteroids. Depending on the preparation used, 10 to 50% of an oral or rectal dose of mesalazine is absorbed. Rapid acetylation in the intestinal wall and liver (t1/2beta 0.5 to 2 hours) and transport probably by P-glycoprotein affect mucosal concentrations of mesalazine, which apparently determine clinical response. Any clinical condition influencing the release and topical availability of mesalazine might modify its therapeutic potential. Metronidazole has high (approximately 90%) oral bioavailability, with hepatic elimination characterised by a t1/2beta of 6 to 10 hours and a total clearance of about 4 L/h/kg. Ciprofloxacin is largely excreted unchanged both renally (about 45% of dose) and extrarenally (25%), with a relatively short t1/2beta (3.5 to 7 hours). Thus, renal function affects the systemic availability of ciprofloxacin. Both mercaptopurine and its prodrug azathioprine are metabolised to active compounds (6-thioguanine nucleotides; 6-TGN) by hypoxanthine-guanine phosphoribosyltransferase and to inactive metabolites by the polymorphically expressed thiopurine S-methyltransferase (TPMT) and xanthine oxidase. Patients with low TPMT activity have a higher risk of developing haemopoietic toxicity. Both mercaptopurine and azathioprine have a short t1/2beta (1 to 2 hours), but the t1/2beta of 6-TGN ranges from 3 to 13 days. Therapeutic response seems to be related to 6-TGN concentration. Almost complete bioavailability has been observed after intramuscular and subcutaneous administration of methotrexate, which is predominantly (85%) excreted as unchanged drug with a t1/2beta of up to 50 hours. Thus, renal function is the major determinant for disposition of methotrexate. Cyclosporin is slowly and incompletely absorbed. It is extensively metabolised by CYP3A4/5 in the liver and intestine (median t1/2beta and clearance 7.9 hours and 0.46 L/h/kg, respectively), and inhibitors and inducers of CYP3A4 can modify response and toxicity. Infliximab is predominantly distributed to the vascular compartment and eliminated with a t1/2beta between 10 and 14 days. No accumulation was observed when it was administered at intervals of 4 or 8 weeks. Methotrexate may reduce the clearance of infliximab from serum.
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PMID:Pharmacokinetic considerations in the treatment of inflammatory bowel disease. 1170 60

The permeability of 19 compounds in both the Caco-2/TC7 and HT29-MTX models was determined, and the ability of each model to predict intestinal absorption in humans was compared. Similar apparent permeability values (log P(app)) were obtained in both models for the majority of compounds tested, and plots of log P(app) versus fraction absorbed in humans gave comparable sigmoidal curves. A linear correlation was also observed between the log P(app) values derived from these two models, which suggests that HT29-MTX is an alternative model for absorption prediction in humans. The similarity of both the diffusion coefficients and permeability values obtained for a range of hydrophilic and lipophilic compounds in the two models indicates that the mucus layer secreted by the human adenocarcinoma HT29-MTX goblet cells does not constitute a diffusion barrier to such compounds. The lack of P-glycoprotein (P-gp) in the HT29-MTX cell line may explain the higher permeability values obtained for cimetidine and sumatriptan in this model compared with those derived from the Caco-2/TC7 monolayers. The results suggest that the HT29-MTX model can be used to rank order the passive permeability of compounds, irrespective of their potential interaction with P-gp, which may facilitate optimization of the physicochemical features of compounds within a chemical series.
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PMID:HT29-MTX and Caco-2/TC7 monolayers as predictive models for human intestinal absorption: role of the mucus layer. 1174 19

This review gives an overview of the current approaches to evaluate drug absorption potential in the different phases of drug discovery and development. Methods discussed include in silico models, artificial membranes as absorption models, in vitro models such as the Ussing chamber and Caco-2 monolayers, in situ rat intestinal perfusion and in vivo absorption studies. In silico models such as iDEA can help optimizing chemical synthesis since the fraction absorbed (Fa) can be predicted based on structural characteristics only. A more accurate prediction of Fa can be obtained by feeding the iDEA model with Caco-2 permeability data and solubility data at various pH's. Permeability experiments with artificial membranes such as the filter-IAM technology are high-throughput and offer the possibility to group compounds according to a low and a high permeability. Highly permeable compounds, however, need to be further evaluated in Caco-2 cells, since artificial membranes lack active transport systems and efflux mechanisms such as P-glycoprotein (PgP). Caco-2 and other "intestinal-like" cell lines (MDCK, TC-7, HT29-MTX, 2/4/A1) permit to perform mechanistic studies and identify drug-drug interactions at the level of PgP. The everted sac and Ussing chamber techniques are more advanced models in the sense that they can provide additional information with respect to intestinal metabolism. In situ rat intestinal perfusion is a reliable technique to investigate drug absorption potential in combination with intestinal metabolism, however, it is time consuming, and therefore not suited for screening purposes. Finally, in vivo absorption in animals can be estimated from bioavailability studies (ratio of the plasma AUC after oral and i.v. administration). The role of the liver in affecting bioavailability can be evaluated by portal vein sampling experiments in dogs.
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PMID:Strategies for absorption screening in drug discovery and development. 1189 3

1. We investigated the hepatobiliary transport of doxorubicin in the isolated perfused liver prepared from the adjuvant arthritis rat, an animal model for rheumatoid arthritis, to examine the hepatic P-glycoprotein activity in the adjuvant arthritis rat. 2. Liver was isolated from the normal and the adjuvant arthritis rat and perfused for 60 min with recirculating buffer and the perfusate and bile samples were collected at timed interval. 3. The elimination of doxorubicin in the adjuvant arthritis rat tended to be reduced, but it was not significantly different from the normal rat. Biliary clearance (CL(bile)) in the normal rat was 1.93 +/- 0.48 ml min(-1), whereas, CL(bile) in the adjuvant arthritis rat was significantly decreased to 0.40 +/- 0.13 ml min(-1). 4. CL(bile) was markedly decreased to about 0.15 ml min(-1) in the presence of 100 microM verapamil in both types of rat. Methotrexate treatment had no effect on CL(bile) in both the normal and adjuvant arthritis rat (2.18 +/- 0.22 and 0.47 +/- 0.22 ml min(-1), respectively). 5. The results suggest that the hepatic P-glycoprotein activity was markedly decreased in the adjuvant arthritis rat and the effect of methotrexate on the hepatic P-glycoprotein activity did not corresponded to its anti-inflammatory effect.
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PMID:Decreased activity of hepatic P-glycoprotein in the isolated perfused liver of the adjuvant arthritis rat. 1248 26

The Y-box binding protein 1 (YB-1) regulates gene expression through transcription and translation. YB-1 has been shown to be associated with up-regulation of P-glycoprotein (Pgp), an ATP-binding transporter involved in multi-drug resistance. In this study, we determined the prognostic significance of YB-1 and its relationship with Pgp in patients with breast cancer. YB-1 and Pgp expression were evaluated by immunohistochemistry in resected specimens of infiltrative ductal breast cancers from 99 patients and 57 patients respectively and correlated with clinicopathological parameters and adjuvant chemotherapy regimes. The antibody for the YB-1 protein was prepared by injecting a rabbit with a purified recombinant chicken YB1 protein. The relationship between YB-1 and Pgp was also evaluated by a computational approach using the Resonant Recognition Model (RRM). We found that breast tumors which were both estrogen receptor-negative and lymph node positive were associated with high YB-1 expression (P=0.017). In patients who did not receive adjuvant chemotherapy, recurrence risk was reduced in breast cancers having lower YB-1 expression (P=0.034), suggesting that high levels of YB-1 expression in breast cancer is associated with tumor aggressiveness. We were able to demonstrate a direct interaction between YB-1 and Pgp using the computer-based RRM. Interestingly, we found that patients who were on a chemotherapy regime which contained an anthracycline (a Pgp substrate) and subsequently developed recurrence, had a higher YB-1 score compared to patients on the Cyclophosphamide/Methotrexate/5-Fluorouracil regime (P=0.024). YB-1 expression in breast cancer may be a potential marker of chemoresistance and could possibly aid in selection of the appropriate adjuvant chemotherapy regime for breast cancers.
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PMID:Y-box binding protein, YB-1, as a marker of tumor aggressiveness and response to adjuvant chemotherapy in breast cancer. 1570 14

Multistep tumorigenesis is a form of microevolution consisting of mutation and selection. To clarify the role of selection modalities in tumor development, we examined two alternative evolutionary conditions, r-selection in sparse culture, which allows cells to proliferate rapidly, and K-selection in confluent culture, in which overcrowding constrains cell proliferation. Using MYC- and EJ-RAS-transformed rat embryo fibroblasts, we found that K-selected cells acquired and stably maintained multidrug resistance (MDR) to DOX, VCR, MTX and Ara-C. Then, we examined the involvement of a number of factors potentially causal of the development of MDR, that is, ploidy, Tp53 mutation, doubling time and the expression levels of genes related to drug resistance. Although ploidy status and Tp53 mutations did not correlate with MDR, we found that Abcb1/Mdr1, encoding P-glycoprotein (Pgp), was significantly upregulated after K-selection. Cyclosporin A, a competitive inhibitor of Pgp, increased the intracellular accumulation of DOX and reduced the resistance to it. Indeed, the population of Pgp-transfected cells significantly expanded under K-, but not under r-selection. In addition to Pgp upregulation, altered expression of other genes such as Cda/cytidine deaminase and Slc29a1/equilibrative nucleoside transporter 1 and prolonged doubling times were associated with MDR. This system reproduces events associated with MDR in vivo and would be useful for analysis of MDR development.
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PMID:Development of multidrug resistance due to multiple factors including P-glycoprotein overexpression under K-selection after MYC and HRAS oncogene activation. 1635 56

The objective of this study was to investigate whether cyclosporin A (CsA) is a modulator for breast cancer resistance protein (BCRP). The interactions between CsA and BCRP were evaluated by using both membrane- and cell-based assays. CsA inhibited BCRP or BCRP R482T mutant-associated ATPase with an IC(50) of 26.1 and 7.3 microM (31,388 and 8779 ng/ml), respectively, indicating that CsA is a modulator for BCRP and its R482T mutant. The apparent permeability (P(app)) of CsA was not affected by the BCRP-specific inhibitor Ko143 in both apical-to-basolateral (A-to-B) and basolateral-to-apical (B-to-A) directions in hBCRP- or mBcrp-transfected MDCKII cells, whereas CsA at 50 microM significantly increased the A-to-B transport and decreased B-to-A transport of BCRP substrates, [(3)H]estrone-3-sulfate ([(3)H]E3S) and [(3)H]methotrexate ([(3)H]MTX), in hBCRP- and mBcrp1-trasfected MDCKII cells. Similar to cellular transport studies, CsA did not exhibit ATP-dependent uptake in BCRP-expressed membrane vesicles but inhibited the ATP-mediated E3S and MTX uptake in the same vesicles. The inhibitory constant (K(i)) of CsA toward BCRP was 6.7 microM (8507 ng/ml) and 7.8 microM (9380 ng/ml) when using E3S or MTX, respectively, as a BCRP substrate. The inhibitory potency of CsA on BCRP wild type or its R482T mutant was lower than that on P-glycoprotein. The present studies demonstrate that CsA is an inhibitor but not a substrate for BCRP, and has low potential to cause drug-drug interactions with BCRP substrate drugs due to its weak inhibitory effect on BCRP and BCRP R482T mutant at its normal therapeutic blood concentrations (200-400 ng/ml) (Blood 91:362-363, 1998).
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PMID:Interactions of cyclosporin a with breast cancer resistance protein. 1722 Feb 44

Ferulic acid is an important antioxidant found in food, beverages, supplements, and herbal medicines. However, its mechanism of absorption in the colon has never been examined, even though this is its main site of in vivo absorption. Ferulic acid was efficiently transported as the free form through an in vitro model for the colonic epithelium consisting of cocultured Caco-2 and mucus-producing HT29-MTX cells, with only a small amount transported as feruloyl-glucuronide or sulfate, together with some free dihydroferulic acid. This pattern of metabolism and permeation was also seen with the use of rat everted ascending and descending colon sacs. In the cell model, free ferulic acid permeated by passive diffusion, as judged by the linearity of the uptake over time and nonsaturable concentration dependence. The permeation was independent of tight junctions but strongly linked to the hydrophobicity of the different phenolic acids tested, suggesting a transcellular rather than a paracellular transport. Using inhibitors, we showed that only a small proportion (<20%) of the free ferulic acid transport was carrier-mediated. The production of metabolites in the basal chamber was lowered by 3-[[3-[2-(7-chloroquinolin-2-yl)-vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571) and increased by cyclosporin A, implying an involvement of multidrug resistance protein and P-glycoprotein transporters in the efflux of metabolites, respectively to the serosal and luminal sides. These results show that the form of ferulic acid available to the blood after passage across the colonic barrier would be mainly the free form, together with only a small percentage of conjugated and reduced ferulic acid.
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PMID:Transport and metabolism of ferulic acid through the colonic epithelium. 1795 26

Secondary resistance may be a major problem in the management of autoimmune diseases. P-glycoprotein (P-gp) over-function has been described as a mechanism of drug resistance in autoimmune patients. P-gp function can in vitro be inhibited by cyclosporine A (CSA) and verapamil; moreover, P-gp reduction by CSA in systemic lupus erythematosus and rheumatoid arthritis has been demonstrated. Here, P-gp function before and after CSA administration in three psoriatic arthritis (PsA) patients, who developed a resistance to MTX/SSA, has been evaluated. P-gp function on patient cells was analyzed by measuring the changes in rhodamine-123 (Rh-123) fluorescence after verapamil incubation. CSA treatment resulted in good clinical outcome that was related with a significant P-gp function reduction at CD3+ and CD8+ levels. In addition to its immunosuppressive activity, CSA results may also be related to MTX/SSA effect restoration through P-gp inhibition. This is the first time that CSA has been demonstrated as being able to revert MTX/SSA resistance in PsA.
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PMID:Reversion of resistance to immunosuppressive agents in three patients with psoriatic arthritis by cyclosporine A: modulation of P-glycoprotein function. 2106 75


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