Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High response rates are seen in patients undergoing dose-intensive chemotherapy and autologous marrow transplantation due to the ability of the therapy to overcome inherent or acquired drug resistance. However, relapse rates are also high because this drug resistance reversal is incomplete. Because both P-glycoprotein- and platinum-induced resistance appear to be clinically important and can be reversed in vitro with a short exposure of cyclosporin A (CSA) at 2000 and 5000 ng/ml, respectively, we undertook a trial of high-dose chemotherapy with carboplatin (1500mg/m2), mitoxantrone (75 mg/m2), and cyclophosphamide (120 mg/kg) over a 5-day period combined with escalating doses of CSA. Thirty-seven patients with primarily breast cancer (61% doxorubicin resistant) and ovarian cancer (85% platinum resistant) were treated with CSA given as a bolus 18 h prior to chemotherapy, followed by a 5-day infusion at doses of 5.0-28.2 mg/kg/day and the chemotherapy. The maximum tolerated dose of CSA was a bolus of 5.5 mg/kg and an infusion of 15. 9 mg/kg/day, which gave a mean serum CSA level of 1544 ng/ml. The dose-limiting toxicity was severe mucositis and enteritis, leading to infectious complications. Nephrotoxicity was seen in 42% and, while usually mild and reversible, was fatal in two patients with pretreatment creatinine clearances h80 ml/min. Grade III-IV isolated hyperbilirubinemia was seen in 39%, but appeared to be of no clinical significance. The overall response rate for the 26 patients with measurable/evaluable disease was 73% and 63% for those with doxorubicin- or platinum-resistant disease. The median overall survival and progression-free survival for the group were 18.1 and 8. 0 months. The overall survival for the nine patients with doxorubicin-resistant breast cancer was 19.3 months. Although we did not achieve CSA levels needed to reverse platinum resistance in vivo, levels approaching those needed to reverse P-glycoprotein resistance were reached at the maximum tolerated dose. The strategy of combining dose intensity with drug resistance reversal deserves further study, especially with the advent of potentially less toxic agents available to reverse P-glycoprotein-mediated resistance.
 ...
PMID:High-dose chemotherapy combined with escalating doses of cyclosporin A and an autologous bone marrow transplant for the treatment of drug-resistant solid tumors: a phase I clinical trial. 981 49

We encountered two cases of pediatric living-related liver transplant recipients who showed increases in blood concentration of cyclosporine or tacrolimus, a dual substrate for cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), during a diarrheal episode. To investigate the effect of intestinal inflammation on the metabolic and efflux pump activities, we conducted the experiments using the lipopolysaccharide (LPS)-induced intestinal damage model. Intestinal epithelial CYP3A activity was assessed by nifedipine oxidation using intestinal epithelial microsomes in rat. Drug efflux by P-gp was tested using digoxin flux with the excised intestine perfusion system in rats. Intraperitoneal injection of LPS (0.3 mg/kg) significantly reduced the intestinal epithelial CYP3A activity by 41% (p < 0.01). In the proximal jejunal segment of the rats treated with LPS, mucosal to serosal flux of digoxin was significantly enhanced compared to that of control (p < 0.05). Efflux of digoxin, which was taken up by intestinal epithelium, to mucosal perfusate was significantly blunted in the jejunum treated with LPS (p < 0.05), which indicates that the LPS treatment reduced the P-gp activity in rat small intestine. These findings suggest that the suppression of CYP3A and P-gp activities may be involved in the mechanism of elevated blood concentrations of cyclosporine and tacrolimus during enteritis-induced diarrhea. To prevent a drug-induced adverse effect, dose of a drug, which is a substrate of CYP3A or P-gp, should be reduced during such an episode.
 ...
PMID:Elevated blood concentrations of calcineurin inhibitors during diarrheal episode in pediatric liver transplant recipients: involvement of the suppression of intestinal cytochrome P450 3A and P-glycoprotein. 1591 Mar 87

Inflammatory bowel disease (IBD) is an idiopathic chronic inflammatory disease of the stomach, the small intestine and/or the large intestine. Loss of integrity of the intestinal barrier may be an important factor in the pathogenesis of IBD. In dogs, lymphoplasmacytic enteritis (LPE) is one of the recognized forms of IBD. P-glycoprotein (P-gp) is a membrane-bound efflux pump constituting an important component of the intestinal barrier. Changes in P-gp expression at the level of the intestinal barrier may be important in the pathogenesis of canine LPE, as this may lead to variable protection against xenobiotics and bacterial products in the intestine. The aim of the present study was to evaluate the expression of epithelial P-gp in the intestine in dogs with LPE compared with disease-free animals. Formalin-fixed intestinal biopsy samples from 57 dogs with histopathological evidence of LPE were immunolabelled with anti-P-gp antibodies (C494 and C219). Endoscopic biopsy samples of the duodenum and colon from 16 healthy beagles were used as controls. None of the control dogs had P-gp expression in the apical membrane of duodenal enterocytes, but all had P-gp labelling at the colonic epithelial surface. Twenty out of 57 dogs with LPE had P-gp expression at the apical surface membrane of villus epithelial cells in the duodenum, jejunum and/or ileum. Six out of 16 colonic samples from dogs with LPE had decreased P-gp expression at the epithelial surface compared with controls. It is unclear whether these changes in P-gp expression in dogs with LPE are a cause or a consequence of the inflammation. The observed changes could affect bioavailability of therapeutic drugs used in LPE.
 ...
PMID:Expression of P-glycoprotein in the intestinal epithelium of dogs with lymphoplasmacytic enteritis. 2133 3