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 report a case of ectopic salivary amylase-producing IgA- lambda-type multiple myeloma. A 70-year-old man was admitted because of anemia and renal failure. After chemotherapy for eight months, the serum amylase markedly increased. Amylase activity in the supernatant of cultured myeloma cells, which were obtained from the bone marrow, also increased. The myeloma cells expressed MDR-1/P-glycoprotein). The case implies the association of drug resistance and the ectopic amylase production in a case of multiple myeloma.
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PMID:[Ectopic salivary amylase-producing IgA- lambda-type multiple myeloma with expression of MDR-1/P-glycoprotein]. 171 26

In the kidney, endothelins (ETs) are important regulators of blood flow, glomerular hemodynamics, and sodium and water homeostasis. They have been implicated in the pathophysiology of acute ischemic renal failure, nephrotoxicity by cyclosporine, cisplatin and radiocontrast agents, and vascular rejection of kidney transplants. Here, we used intact killifish renal proximal tubules, fluorescent substrates for Mrp2 (fluorescein-methotrexate, FL-MTX) and P-glycoprotein (a fluorescent CSA derivative, NBD-CSA), and confocal microscopy to reveal a new role for renal ET: regulation of ATP-driven drug transport in proximal tubule. Subnanomolar to nanomolar concentrations of ET-1 rapidly reduced the cell-to-tubular lumen transport of both fluorescent compounds. These effects were prevented by an ET(B) receptor antagonist but not by an ET(A) receptor antagonist. Immunostaining with an antibody to mammalian ET(B) receptors showed specific localization to the basolateral membrane of the fish tubular epithelial cells. ET-1 effects on transport were blocked by protein kinase C-selective inhibitors, implicating protein kinase C in ET-1 signaling. Finally, the nephrotoxic radiocontrast agent iohexol reduced cell-to-lumen FL-MTX and NBD-CSA transport, and these effects were abolished by an ET(B) receptor antagonist. These are the first results linking ET to the control of xenobiotic transport and the first demonstrating control of renal multidrug resistance-associated protein 2 and P-glycoprotein by a hormone.
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PMID:Endothelin B receptor-mediated regulation of ATP-driven drug secretion in renal proximal tubule. 1061 79

The effect of glycerol-induced acute renal failure on P-glycoprotein expression and function was evaluated in rats. The in vivo function of P-glycoprotein was evaluated by measuring renal secretory and biliary clearance and brain distribution of rhodamine 123 (Rho-123), a P-glycoprotein substrate, under a steady-state plasma concentration. In acute renal failure rats, the P-glycoprotein level increased 2.5-fold in the kidney, but not in the liver and brain. In contrast, P-glycoprotein function in these tissues was suppressed. Interestingly, not only the renal but also the biliary clearance of Rho-123 was correlated with the glomerular filtration rate. In Caco-2 cells, plasma from renal failure rats exhibited a greater inhibitory effect on P-glycoprotein-mediated transport of Rho-123 than did plasma from control rats. In conclusion, P-glycoprotein function was systemically suppressed in acute renal failure, even though the level of P-glycoprotein remained unchanged or rather increased. This may be due to the accumulation of some endogenous P-glycoprotein substrates/modulators in the plasma in disease states.
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PMID:Expression and function of P-glycoprotein in rats with glycerol-induced acute renal failure. 1104 Mar 53

Renal failure not only alters the renal elimination, but also the non-renal disposition of drugs that are extensively metabolized by the liver. Although reduced metabolic enzyme activity in some cases can be responsible for the reduced drug clearance, alterations in the transporter systems may also be involved in the process. With the development of renal failure, the renal secretion of organic ions mediated by organic anion transporters (OATs) and organic cation transporters (OCTs) is decreased. 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) and other organic anionic uremic toxins may directly inhibit the renal excretion of various drugs and endogenous organic acids by competitively inhibiting OATs. In addition, the expression of OAT1 and OCT2 was reduced in chronic renal failure (CRF) rats. Renal failure also impairs the liver uptake of drugs and organic anions, such as bromosulphophthalein (BSP), indocyanine green (ICG), and thyroxine, where organic anion transport polypeptides (OATPs) are the major transporters. Most previous studies have been done in animals or cell culture, very often in rat models, but these are presumed to reflect the presentation of advanced renal disease in humans as well. Recent studies demonstrate that the uremic toxins CMPF and indoxyl sulfate (IS) can directly inhibit rOatp2 and hOATP-C in hepatocytes. The protein content of the liver uptake transporters Oatp1, 2, and 4 were significantly decreased in CRF rats. Decreased activity of the intestinal efflux transporter, P-glycoprotein (P-gp), was also observed in CRF rats, with no significant change of protein content, suggesting that uremic toxins may suppress P-gp function. However, increased protein levels of multidrug resistance-associated protein (MRP) 2 in the kidney and MRP3 in the liver were found in CRF rats, suggesting an adaptive response that may serve as a protective mechanism. Increases in drug areas under the curve (AUCs) in subjects with advanced renal disease for drugs that are not renally excreted are consistent with uremic toxin effects on either intestinal or hepatic cell transporters, metabolizing enzymes, or both. In conclusion, alterations of drug transporters, as well as metabolic enzymes, in patients with renal failure can be responsible for reduced drug clearance.
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PMID:Effects of renal failure on drug transport and metabolism. 1608 15

Renal mass reduction is associated with a compromise in renal excretion, and thus dosages of drugs need to be adjusted to avoid adverse reactions and to ensure their effectiveness. A prototypic example is patients who had undergone transplantation due to a variety of causes, including diabetic nephropathy; the latter appears to be the major cause of renal failure requiring hemodialysis and transplantation. Conceivably, hyperglycemia with reduced renal mass interferes in the delivery of xenobiotics handled by various tubular transporters. In this investigation, effect of renal mass reduction/hyperglycemia on gene and protein expression of P-glycoprotein (Pgp), PEPT1, and PEPT2 was assessed. Also, [H(3)]glycylsarcosine uptake, a prototype of dipeptide, was measured in various groups of rats: sham-operated, uninephrectomized, streptozotocin-induced diabetes, and diabetic + uninephrectomized. An increase in Pgp, PEPT1, and PEPT2 expression was observed in kidneys of uninephrectomy rats, the highest being in the Pgp. Similarly, an increase was observed in diabetic rats who had undergone uninephrectomy, although less than those with nephrectomy alone. No differences were observed between sham-operated and diabetic groups. Increased uptake of [H(3)]glycylsarcosine was also seen in uninephrectomised rats. A modest uptake was observed in diabetic rats who had undergone uninephrectomy. The data suggest that uninephrectomy induces an increase in the expression and activity of transporters localized to renal tubular epithelial brush border. The fact that upregulation and activity of the peptide transporters were less in kidneys of diabetic animals who had undergone uninephrectomy compared with uninephrectomy alone suggests that hyperglycemia interferes in their expression and activity during the compensatory phase.
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PMID:Expression and functional characteristics of tubular transporters: P-glycoprotein, PEPT1, and PEPT2 in renal mass reduction and diabetes. 1702 60

P-glycoprotein (P-gp), the product of MDR1 gene, is a protein which mediates transmembrane transport of a great number of xenobiotics including cyclosporin A used as an immunosuppressive drug in patients with allogenic kidney grafts. The P-gp activity and expression is dependent on the MDR1 gene polymorphism in position C3435T of exon 26. In this study, C3435T polymorphism was analyzed in 116 patients with allogenic kidney graft treated with cyclosporin Aand 144 randomly selected healthy individuals. The prevalence of MDR1 gene genotypes 3435CC, 3435CT, 3435TT were also compared in patients after allogenic kidney graft with both acute and chronic graft rejection (48 patients with acute and 76 with chronic graft rejection) and control groups (respectively 139 and 112). The results of the study demonstrated that the allelic frequency and MDR1 genotype distribution were similar in all evaluated groups. It was revealed that MDR1 gene polymorphism was not a predisposing factor for terminal kidney failure leading to renal transplantation. Moreover, evaluation of C3435T polymorphism of MDR1 gene will probably not be useful for characterization of groups of patients at increased risk of acute and chronic kidney graft rejection.
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PMID:Polymorphism in the P-glycoprotein drug transporter MDR1 gene in renal transplant patients treated with cyclosporin A in a Polish population. 1755 98

Introduction. Therapeutic doses of colchicine in patients with renal compromise and cyclosporine therapy may result in increased plasma concentrations of colchicine and colchicine toxicity. Case Report. A 60-year-old heart transplant patient with chronic renal failure and cyclosporine-induced immunosuppression was started on colchicine for suspected gout. Four days later, he developed multi-organ failure with rhabdomyolysis, liver damage, polyneuropathy, and cardiotoxicity. Colchicine intoxication was suspected and plasma levels were 7 ng/mL 36 hours after the sixth dose. Neutropenia with an absolute neutrophil count of 700 cells/mm3 was observed five days after colchicine discontinuation. Drug discontinuation, supportive care, antibiotic therapy for a concurrent infection, and G-CSF administration resulted in recovery and he was discharged from the hospital 3 weeks later. Discussion. Cyclosporine co-administration increases colchicine toxicity by a dual mechanism: cyclosporine inhibits P-glycoprotein resulting in increased intracellular colchicine concentrations and decreased hepatic and renal excretion of the drug and cyclosporine interacts with CYP3A4 to decreases the hepatic elimination of colchicine. On the other hand, colchicine may increase cyclosporine neurotoxicity by an addictive mechanism. Conclusions. Shortterm administration of therapeutic colchicine doses may cause life-threatening side effects in cyclosporine-treated patients with renal failure.
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PMID:Colchicine-induced toxicity in a heart transplant patient with chronic renal failure. 1860 82

(1) Renal failure, either pre-existing or induced by a nephrotoxic drug, increases the risk of adverse effects in patients taking colchicine; (2) Combining colchicines with a macrolide (except for spiramycin) carries a risk of life-threatening pancytopenia; (3) Ciclosporin co-administration can aggravate the neuromuscular adverse effects of colchicine; (4) Combining colchicine with lipid-lowering drugs (statins and fibrates) can cause myopathy; (5) Several mechanisms have been implicated: competition for cytochrome P450 or P-glycoprotein, additive adverse effects (especially on muscle), and colchicine accumulation due to a reduction in its renal excretion; (6) Patients with gout should use colchicine only after failure of symptomatic treatment: ice application, paracetamol, and possibly ibuprofen, a nonsteroidal antiinflammatory drug with well-documented adverse effects; (7) If colchicine is nevertheless used, it should be at the minimum effective dose. Close clinical monitoring is required in order to detect early signs of adverse effects, especially diarrhoea, the earliest sign in patients with renal failure and in the elderly.
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PMID:Colchicine: serious interactions. 1949 85

(1) The standard anticoagulant for preventing thromboembolic events after hip or knee replacement surgery is a subcutaneous low-molecular-weight heparin such as enoxaparin; (2) Dabigatran, a specific thrombin inhibitor, was recently licensed for oral prophylaxis in this setting, as dabigatran etexilate (mesilate), a prodrug; (3) The clinical evaluation of dabigatran in this indication is based on two comparative double-blind trials with similar protocols, comparing dabigatran 150 mg or 220 mg/day versus enoxaparin in 3494 patients undergoing hip replacement surgery and 2101 patients undergoing knee replacement surgery. The results were virtually identical: compared with enoxaparin, dabigatran did not reduce overall mortality (almost zero in the different groups), the frequency of symptomatic pulmonary embolism (almost zero in the different groups), or the frequency of symptomatic deep venous thrombosis (0.1% to 1.2%); (4) There was no difference between the groups with respect to the frequency of severe bleeding (about 1.5%), hepatic disorders (about 4%), or acute coronary events (a few cases). But dabigatran was associated with surgical wound seepage in 7% of patients, versus 4.7% with enoxaparin; (5) The anticoagulant effect of dabigatran, and therefore the frequency of haemorrhage, increases with age and in cases of renal failure. However, clinical trials included relatively few elderly patients and/or patients with renal failure, who nonetheless represent a large proportion of the candidates for hip or knee replacement; (6) Dabigatran becomes more potent when combined with P-glycoprotein inhibitors or with drugs that impair renal function. Combination with other antithrombotic drugs should be avoided. (7) Dabigatran is administered orally, while enoxaparin requires daily subcutaneous injections. Dabigatran therapy does not necessitate laboratory monitoring, while the platelet count must be monitored with enoxaparin. There is no known antidote for dabigatran overdose; (8) In summary, for the prevention of venous thromboembolic events after orthopaedic surgery, it is better to continue to use heparins, at least pending more thorough evaluation of dabigatran.
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PMID:Dabigatran: new drug. Continue to use heparin, a better-known option. 1963 11

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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