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)

Concomitant administration of botanical supplements with drugs that are P-glycoprotein (P-gp) substrates may produce clinically significant herb-drug interactions. This study evaluated the effects of St. John's wort and Echinacea on the pharmacokinetics of digoxin, a recognized P-gp substrate. Eighteen healthy volunteers were randomly assigned to receive a standardized St. John's wort (300 mg three times daily) or Echinacea (267 mg three times daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (300 mg twice daily, 7 days) and clarithromycin (500 mg twice daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin 0.25 mg) was administered orally before and after each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), elimination half-life, and maximum serum concentration were used to assess the effects of St. John's wort, Echinacea, rifampin, and clarithromycin on digoxin disposition. St. John's wort and rifampin both produced significant reductions (p < 0.05) in AUC((0-3)), AUC((0-24)), and C(max), while clarithromycin increased these parameters significantly (p < 0.05). Echinacea supplementation did not affect digoxin pharmacokinetics. Clinically significant P-gp-mediated herb-drug interactions are more likely to occur with St. John's wort than with Echinacea.
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PMID:Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics. 1821 50

Digoxin, a commonly prescribed cardiac glycoside with a narrow therapeutic window, is routinely used in pharmacokinetic studies to assess the in vivo activity of the drug efflux pump P-glycoprotein. To minimize adverse events, a sub-therapeutic dose of digoxin is usually administered, producing low plasma concentrations requiring a sensitive detection technique. Commonly available immunoassay techniques do not provide the required sensitivity to measure these low plasma concentrations and are potentially non-specific in certain subject populations. Previously published mass spectrometric techniques require either large plasma volumes or a tandem mass spectrometer. To overcome these challenges we have developed a sensitive and specific LC-MS method for the quantification of digoxin in small volumes of human plasma and urine. Plasma (1 mL) was extracted with methyl t-butyl ether under basic conditions followed by LC-MS detection of the sodium adducts of digoxin (803.4 m/z) and digitoxin (787.4 m/z, internal standard). Linearity and accuracy were demonstrated across a wide range of digoxin plasma concentration (0.05-1.5 ng/mL). This specific, sensitive, validated digoxin LC-MS assay can be used to quantify sub-therapeutic digoxin plasma concentrations in men and women (pregnant and non-pregnant).
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PMID:Sensitive and specific LC-MS assay for quantification of digoxin in human plasma and urine. 1831 88

Echinacea is widely used as a medical herbal product, but its interaction potential with the drug efflux transporter P-glycoprotein (P-gp) has not yet been evaluated. The interaction potential of Echinacea purpurea towards P-gp mediated drug transport was studied in human intestinal Caco-2 cells. Digoxin (30 nm) was used as a substrate and verapamil as a control inhibitor. Ethanol, 0.8%, needed for herbal extraction and compatibility with the commercial products, inhibited the net digoxin flux by 18%. E. purpurea influenced to a higher degree the B-A transport of digoxin than the A-B transport. A minor increase in net digoxin flux was observed at low concentrations of E. purpurea, an effect anticipated to be allosteric in nature. At higher concentrations, from 0.4 to 6.36 mg dry weight/mL, a statistically significant linear dose-related decrease was observed in the net digoxin flux, indicating a dose dependent E. purpurea inhibition of P-gp. Both Vmax and Km of the net digoxin flux, calculated to 23.7 nmol/cm2/h and 385 microm, respectively, decreased in the presence of E. purpurea in an uncompetitive fashion. Although the effects of Echinacea purpurea on systemic P-gp mediated drug transport are probably limited, an influence on drug bioavailability can not be excluded.
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PMID:Echinacea purpurea and P-glycoprotein drug transport in Caco-2 cells. 1868 89

Although in-vitro experiments have suggested that P-glycoprotein (P-gp) may have an important influence on the disposition of inhaled drugs, the effect of P-gp on absorption from the lung in-vivo has not been reported previously. The aim of this study was to compare the pulmonary absorption of digoxin, a well-characterised substrate for P-gp, in mdr1a (-/-) (P-gp-deficient) and mdr1a (+/+) (P-gp-competent) mice. Digoxin was administered by intratracheal instillation over 3-4 s, a method demonstrated to result in dispersion of the dose to all regions of the lung. Drug distribution was determined in the lungs, plasma, brain, heart, liver and kidney of individual mice after 5, 10, 30, 60 and 90 min. Digoxin was cleared rapidly from the lung after intratracheal administration. No differences were observed in the maximum serum concentrations between mdr1a (+/+) and mdr1a (-/-) mice (37.8 +/- 6.9 and 38.8 +/- 15.8 ng mL(-1), respectively). The serum concentration versus time profiles were similar in both strains; the area under the drug serum concentration versus time curve (AUC) was 2010 and 1812 ng mL(-1) min in mdr1a (-/-) and mdr1a (+/+) mice, respectively. For organs harvested at the end of the experiment (90 min), the only significant difference between the strains was the markedly elevated concentration of digoxin in the brains of mdr1a (-/-) mice. In conclusion, digoxin is rapidly absorbed from the mouse lung following tracheal instillation, with no difference in the rate or extent of absorption between mdr1a-deficient and -competent mice. This suggests that, in contrast to the scenario suggested by in-vitro data, P-gp in the respiratory epithelium may have little influence on the disposition of drugs that are well absorbed from the lung.
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PMID:Lack of difference in pulmonary absorption of digoxin, a P-glycoprotein substrate, in mdr1a-deficient and mdr1a-competent mice. 1881 23

The clinical pharmacokinetics and in vitro inhibition of digoxin were examined to predict the P-glycoprotein (P-gp) component of drug-drug interactions. Coadministered drugs (co-meds) in clinical trials (N = 123) resulted in a small, <or=100% increase in digoxin pharmacokinetics. Digoxin is likely to show the highest perturbation, via inhibition of P-gp, because of the absence of metabolic clearance. In vitro inhibitory potency data (concentration of inhibitor to inhibit 50% P-gp activity; IC(50)) were generated using Caco-2 cells for 19 P-gp inhibitors. Maximum steady-state inhibitor systemic concentration [I], [I]/IC(50) ratios, hypothetical gut concentration ([I(2)], dose/250 ml), and [I(2)]/IC(50) ratios were calculated to simulate systemic and gut-based interactions and were compared with peak plasma concentration (C(max))(,i,ss)/C(max,ss) and area under the curve (AUC)(i)/AUC ratios from the clinical trials. [I]/IC(50) < 0.1 shows high false-negative rates (24% AUC, 41% C(max)); however, to a limited extent, [I(2)]/IC(50) < 10 is predictive of negative digoxin interaction for AUC, and [I]/IC(50) > 0.1 is predictive of clinical digoxin interactions (AUC and C(max)).
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PMID:Drug-drug interactions mediated through P-glycoprotein: clinical relevance and in vitro-in vivo correlation using digoxin as a probe drug. 1898 24

BCRP transports numerous drugs/derived metabolites and toxins, and exhibits overlapping substrate specificity with P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2). Assessing the contribution of BCRP to drug/metabolite biliary excretion in intact hepatocytes remains a challenge. Current studies were designed to develop a novel in vitro tool to specifically assess the contribution of Bcrp to drug biliary excretion. Adenoviral vectors expressing short hairpin (sh) RNA targeting Bcrp (Ad-si01Bcrp) or a nontarget control (Ad-siNT) were packaged and infected into sandwich-cultured rat hepatocytes (SCRH). Protein levels were detected by immunoblot. Biliary excretion index (BEI) and in vitro biliary clearance (Cl(biliary)) of nitrofurantoin (BCRP substrate) and digoxin (P-gp substrate) were compared among noninfected, Ad-siNT- and Ad-si01Bcrp-infected SCRH. shRNA targeting Bcrp efficiently knocked down Bcrp in SCRH, while levels of other transport proteins (P-gp, Mrp2, Bsep, Mrp4 and Oatp1a1) were unaffected. In SCRH exhibiting Bcrp knockdown, cellular accumulation of nitrofurantoin was increased markedly and nitrofurantoin BEI and in vitro Cl(biliary) were decreased to 11% and 14% of control, respectively. Digoxin values were unaffected by knockdown of Bcrp. Results indicated that Bcrp in SCRH contributed predominantly to nitrofurantoin biliary excretion, but played a negligible role in digoxin biliary excretion. In summary, Bcrp knockdown in SCRH is the first in vitro model utilizing intact hepatocytes to assess the contribution of Bcrp to the biliary excretion of drugs. This approach may be useful in predicting drug-drug interactions in biliary excretion and the consequence of impaired BCRP function on the hepatic exposure of drugs/derived metabolites.
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PMID:Knocking down breast cancer resistance protein (Bcrp) by adenoviral vector-mediated RNA interference (RNAi) in sandwich-cultured rat hepatocytes: a novel tool to assess the contribution of Bcrp to drug biliary excretion. 1910 22

Digoxin and ouabain are cardioactive glycosides, which inhibit the Na+/K+-ATPase pump and in this way they increase the intracellular concentration of cytosolic calcium ([Ca2+](i)). They are also strong inducers of the P-glycoprotein (Pgp), a transmembrane transporter which extrudes several drugs, including anticancer agents like doxorubicin. An increased amount of Pgp limits the absorption of drugs through epithelial cells, thus inducing resistance to chemotherapy. The mechanism by which cardioactive glycosides increase Pgp is not known and in this work we investigated whether digoxin and ouabain elicited the expression of Pgp with a calcium-driven mechanism. In human colon cancer HT29 cells both glycosides increased the [Ca2+](i) and this event was dependent on the calcium influx via the Na+/Ca2+ exchanger. The increased [Ca2+](i) enhanced the activity of the calmodulin kinase II enzyme, which in turn activated the transcription factor hypoxia-inducible factor-1alpha. This one was responsible for the increased expression of Pgp, which actively extruded doxorubicin from the cells and significantly reduced the pro-apoptotic effect of the drug. All the effects of glycosides were prevented by inhibiting the Na+/Ca2+ exchanger or the calmodulin kinase II. This work clarified the molecular mechanisms by which digoxin and oubain induce Pgp and pointed out that the administration of cardioactive glycosides may widely affect the absorption of drugs in colon epithelia. Moreover, our results suggest that the efficacy of chemotherapeutic agent substrates of Pgp may be strongly reduced in patients taking digoxin.
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PMID:Digoxin and ouabain induce P-glycoprotein by activating calmodulin kinase II and hypoxia-inducible factor-1alpha in human colon cancer cells. 1964 9

ABSTRACT Aside from acute occupational exposure, an important part of the population may be chronically exposed to the trace amounts of organophosphorothionate pesticides (OPTs) via residues in nutrients and drinking water. P-glycoprotein (P-gp) is a transmembrane protein responsible for the efflux of numerous drugs. OPTs were shown to inhibit P-gp function in vitro and increase its expression in vivo. Digoxin is a probe drug for the investigation of P-gp. To evaluate the effect of repeated low-dose OPT exposure on P-gp, commercial formulations of diluted OPT or tap water were administered to female Wistar rats for 8 consecutive days. On the ninth day each group was further divided into two groups and digoxin was administered either intraduodenally (ID) or intravenously (IV). Blood sampling and bile and urine collection were taken during 6 h at various intervals. The peak concentration in serum (C(max)) of digoxin was found to be decreased and the mean absorption time (MAT) was significantly increased in the digoxin OPT group. The mean residence time was significantly elevated in the digoxin(ID) OPT group. The biliary excretion% digoxin was significantly increased in the digoxin OPT group, while the renal excretion% digoxin rose only in the digoxin(ID) OPT group. No significant differences in time to reach C(max) (t(max)), area under the plasma concentration-time curve (AUC)(0-360), area under the moment curve (AUMC)(0-360), and bioavailability (F) were detected. In our study, repeated low-dose OPT exposure reduced the absorption and increased the excretion% digoxin, which may be related to enhanced P-gp expression. However, alterations of digoxin pharmacokinetic parameters did not change the systemic availability of digoxin.
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PMID:Effect of repeated low-dose organophosphorothionate pesticide exposure on digoxin pharmacokinetics in rats; a possible interaction involving p-glycoprotein. 2002 Aug 72

Drug transporters are involved in clinically relevant drug-drug interactions. P-glycoprotein (P-gp) is an efflux transporter that displays genetic polymorphism. Phenotyping permits evaluation of real-time, in vivo P-gp activity and P-gp-mediated drug-drug interactions. Digoxin, fexofenadine, talinolol and quinidine are commonly used probe drugs for P-gp phenotyping. Although current regulatory guidance documents highlight methodologies for evaluating transporter-based drug-drug interactions, whether current probe drugs are suitable for phenotyping has not been established, and validation criteria are lacking. This review proposes validation criteria and evaluates P-gp probes to determine probe suitability. Based on these criteria, digoxin, fexofenadine, talinolol and quinidine have limitations to their use and are not recommended for P-gp phenotyping.
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PMID:Evaluation of in vivo P-glycoprotein phenotyping probes: a need for validation. 2021 7

Digoxin has a narrow therapeutic margin and potentially life-threatening cardiac adverse effects. Gastrointestinal disorders, neuropsychological disorders and bradycardia are warning signs. Some drug combinations can aggravate the cardiac adverse effects of digoxin, or reduce its efficacy. We reviewed the literature, using the standard Prescrire methodology, in order to examine which drugs are involved in these interactions, and the mechanisms involved. Most relevant data are based on small pharmacokinetic studies or detailed case reports. The adverse effects of digoxin are potentiated by renal impairment, which may be pre-existing or due to nephrotoxic drugs such as nonsteroidal antiinflammatory drugs (NSAIDs), angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II receptor antagonists and ciclosporin. Some coadministered drugs such as macrolides and cardiovascular drugs (especially amiodarone) can cause digoxin overdose through pharmacokinetic interactions. The mechanism most often implicated is inhibition of P-glycoprotein, of which digoxin is a substrate. Hypercalcaemia and hypokalaemia inducing drugs, heart-rate lowering drugs, and drugs that prolong the QT interval or slow cardiac conduction can potentiate the cardiac adverse effects of digoxin. Plasma concentration of digoxin is not affected. Several drugs, including sucralfate, acarbose, cytotoxic agents, and enzyme inducers, can reduce digoxin plasma concentrations. This effect is attributed to decreased gastrointestinal absorption or increased elimination of digoxin. In practice, patients treated with digoxin, and their caregivers, should be aware that digoxin has a narrow therapeutic margin and frequent and potentially severe adverse effects. Close clinical monitoring is necessary to detect early warning signs (bradycardia and gastrointestinal or neurological disorders). Digoxin assay alone is not always sufficient. Special care is required for patients with renal failure, the elderly and patients receiving potentially interacting drugs.
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PMID:Digoxin: serious drug interactions. 2056 89


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