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)

Tubular function is altered in chronic renal failure (CRF). Whether drug secretion by renal tubules is modified in CRF is questioned because of frequent accumulation of various toxins in CRF. This function mainly involves ATP-dependent drug transporters, particularly P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) 2, both present in apical membrane of epithelial cells. The present study was aimed at determining the changes in P-gp and MRP2 expression induced by experimental CRF in kidney and liver. The relationship between MRP2 and glutathione metabolism changes was examined because MRP2 transports GSSG and glutathione conjugates. Rats underwent either 80% subtotal nephrectomy (Nx) or sham operation, and determinations were performed 3 and 6 wk later. CRF induced a 70--200% rise in protein and mRNA expression of MRP2 after 3 and 6 wk post-Nx in remnant kidney and after 6 wk in liver. However, P-gp expression was unchanged by CRF. Relative to whole kidney mass, total MRP2 levels decreased by only 27% in Nx rats whereas total P-gp levels were reduced by 60%. Renal GSSG and total glutathione levels were increased by 30% in Nx rats, but glutathione-S-transferase (GST) activity was normal; liver GSSG levels and GST activity were reduced in Nx rats. In conclusion, CRF resulted in specific overexpression of MRP2 in kidney and liver. This could be an adaptative response to some elevated circulating toxins. The later MRP2 induction and different glutathione changes in liver compared with kidney suggest different mechanisms for MRP2 induction and/or action in these two tissues.
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PMID:Two apical multidrug transporters, P-gp and MRP2, are differently altered in chronic renal failure. 1124 55

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

Neuromyopathy is a rare side effect of chronic colchicine therapy, most often occurring in patients with chronic renal failure. Drugs interacting with colchicine metabolism through CYP(3)A(4) and P-glycoprotein can accelerate accumulation and toxicity. We describe a case of an interaction between clarithromycin and colchicine resulting in acute neuromyopathy, and we conclude that combined use of macrolides and colchicine should be avoided.
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PMID:Colchicine-induced neuromyopathy in a patient with chronic renal failure: the role of clarithromycin. 1849 Jul 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

We report a case of colchicine-induced rhabdomyolysis in a heart/lung-transplanted man treated with cyclosporin. A treatment was to resolve an acute gouty arthritis and was started with 3 mg of colchicine the first day, then 2 mg the second and the third day, and finally 1 mg/d during 6 days. Eight days later, the patient developed multiple organ failure and rhabdomyolysis. The concentration of colchicine analyzed was greater than the standard 153 hours after his last intake. Pharmacokinetic interactions are responsible of this toxicity. Cyclosporin, pravastatin, and azithromycin are known to inhibit P-glycoprotein, which will enhance the intracellular colchicine level by acting in its bioavailability and moderating hepatic and renal excretion. Moreover, long-term treatment by cyclosporin generates chronic renal failure that will, in the same time, decrease colchicine elimination. Even short-term administration of therapeutic colchicine dose may cause colchicine-related toxicity, especially in the setting of a renal failure and/or polymedicinal treatment.
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PMID:Colchicine-induced rhabdomyolysis in a heart/lung transplant patient with concurrent use of cyclosporin, pravastatin, and azithromycin. 2116 52

Studies demonstrated that chronic renal failure (CRF) affects the expression and activity of intestinal, hepatic, and renal drug transporters. Such drug transporters are expressed in brain cells and at the blood-brain barrier (BBB), where they limit the entry and distribution of drugs in the brain. Perturbations in brain drug transporter equilibrium by CRF could lead to central drug toxicity. This study evaluates how CRF affects BBB drug transporters using a 5/6 nephrectomized rat model. Protein and mRNA expression of influx transporters [organic anion-transporting polypeptide (Oatp), organic anion transporter (Oat)] and efflux transporters [P-glycoprotein (P-gp), multidrug resistance-related protein (Mrp), breast cancer resistance protein (Bcrp)] were measured in CRF and control rat brain. Intracerebral accumulation of radiolabeled benzylpenicillin, digoxin, doxorubicin, and verapamil was used to evaluate BBB drug permeability. Protein expression of the transporters was evaluated in rat brain endothelial cells (RBECs) and astrocytes incubated with control and CRF rat serum. We demonstrated significant decreases (30-50%) in protein and mRNA levels of Bcrp, Mrp2 to -4, Oat3, Oatp2 and -3, and P-gp in CRF rat brain biopsies, as well as in astrocytes and RBECs incubated with CRF serum. These decreases did not correlate with in vivo changes because BBB permeability of benzylpenicillin was decreased by 30% in CRF rats, whereas digoxin, doxorubicin, and verapamil permeabilities were unchanged. It thus seems that even with decreased drug transporters, BBB integrity and function is conserved in CRF.
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PMID:Effects of chronic renal failure on brain drug transporters in rats. 2196 19