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)

A growing body of evidence indicates that expression of the mdr1 gene, which encodes the multidrug transporter, P-glycoprotein, contributes to chemotherapeutic resistance of human cancers. Expression of this protein in normal tissues such as the biliary tract, intestines, and renal tubules suggests a role in the excretion of toxins. Modulation of P-glycoprotein function in normal tissues may lead to decreased excretion of drugs and enhanced toxicities. A clinical trial of etoposide with escalating doses of cyclosporine (CsA) as a modulator of multidrug resistance was performed. CsA was delivered as a 2-hour loading dose followed by a 60-hour intravenous infusion, together with etoposide administered as a short infusion daily for 3 days. Patients received one or more courses of etoposide alone before the combined therapy to establish their clinical resistance to etoposide and to study etoposide pharmacokinetics without and then with CsA. Plasma and urinary etoposide was measured by high-performance liquid chromatography and plasma CsA by a nonspecific immunoassay. Conclusions from the initial phase I trial with the use of CsA as a modulator of etoposide are: (1) Serum CsA steady-state levels of up to 4800 ng/ml (4 microM) could be achieved with acceptable toxicity. (2) Toxicities caused by the combined treatment included increased nausea and vomiting, increased myelosuppression, and hyperbilirubinemia, consistent with modulation of P-glycoprotein function in the blood-brain barrier, hematopoietic stem cell, and biliary tract. Renal toxicity was uncommon, but severe in two patients with steady-state plasma CsA levels above 6000 ng/ml. (3) CsA administration had a marked effect on the pharmacokinetics of etoposide, with a doubling of the area under the concentration-time curve as a result of both decreased renal and nonrenal clearance, necessitating a 50% dose reduction in patients with normal renal function and hepatic function. (4) The recommended dose of CsA is a 6-7 mg/kg loading dose administered as a 2-hour intravenous infusion followed by a continuous infusion of 18-21 mg/kg/day for 60 hours with adjustments in the infusion rate to maintain steady-state serum levels of 3000-4800 ng/ml (2.5-4.0 M). We are performing additional phase I trials combining CsA with single-agent doxorubicin and taxol, and the CsA analog PSC-833 with various multidrug-resistant-related cytotoxins.
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PMID:Clinical trials of modulation of multidrug resistance. Pharmacokinetic and pharmacodynamic considerations. 790 6

Anthracyclines are widely used and effective antineoplastic drugs. Although active against a wide variety of solid tumours and haematological malignancies, their clinical use is hindered by tumour resistance and toxicity to healthy tissue. Modification of the general anthracycline ring structure results in analogues with different but overlapping antitumour and tolerability profiles. Activity of the anthracyclines is related to topoisomerase II inhibition, which occurs as a result of anthracycline intercalation between adjacent DNA base pairs. Production of hydroxyl free radicals is associated with antitumour effects and toxicity to healthy tissues. Myocardial tissue is particularly susceptible to free radical damage. Development of tumour cell resistance to anthracyclines involves a number of mechanisms, including P-glycoprotein-mediated resistance. The classical dose-limiting adverse effects of this class of drugs are acute myelosuppression and cumulative dose-related cardiotoxicity. Anthracycline-induced cardiomyopathy is often irreversible and may lead to clinical congestive heart failure. Other toxicities of the anthracyclines, including stomatitis, nausea and vomiting, alopecia and 'radiation recall' reactions, are generally reversible. Anthracycline-induced cardiotoxicity may be reduced or prevented by an administration schedule that produces low peak plasma drug concentrations. Administration of dexrazoxane also provides cardioprotection. Dose intensification of anthracyclines may partly overcome resistance but is associated with reduced tolerability. Liposomal encapsulation of doxorubicin or daunorubicin alters the pharmacokinetic properties of the drugs. Increased distribution in tumours, prolonged circulation and reduced free drug concentrations in plasma may increase antitumour activity and improve the tolerability of the anthracyclines.
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PMID:Anthracyclines in the treatment of cancer. An overview. 936 55

Aprepitant is a highly selective neurokinin-1 receptor antagonist that, in combination with a corticosteroid and a 5-hydroxytryptamine3 (5HT3) receptor antagonist, has been shown to be efficacious in the prevention of highly emetogenic chemotherapy-induced nausea and vomiting. In vitro data suggest that aprepitant is a substrate and a weak inhibitor of P-glycoprotein. Thus, the effect of aprepitant on the pharmacokinetics of digoxin, a P-glycoprotein substrate, was examined in a double-blind, placebo-controlled, randomized, two-period crossover study in 12 healthy subjects. Each subject received daily oral doses of digoxin 0.25 mg on Days 1 through 13 during both treatment periods. Aprepitant 125 mg (or matching placebo) was coadministered orally with digoxin on Day 7, and aprepitant 80 mg (or matching placebo) was coadministered orally with digoxin on Days 8 to 11. Aprepitant did not affect the pharmacokinetics of digoxin. The geometric mean ratios (90% confidence interval [CI]) for plasma AUC0-24 h of digoxin (with/without aprepitant) were 0.99 (0.91, 1.09) and 0.93 (0.83, 1.05) on Days 7 and 11, respectively, and the geometric mean ratios (90% CI) for the 24-hour urinary excretion of immunoreactive digoxin (with/without aprepitant) were 0.91 (0.80, 1.04) and 1.00 (0.91, 1.09) on Days 7 and 11, respectively. Thus, aprepitant, when dosed as a 5-day regimen, did not interact with a known substrate of the P-glycoprotein transporter.
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PMID:Lack of effect of aprepitant on digoxin pharmacokinetics in healthy subjects. 1295 48

BMS-184476 is a 7-methylthiomethyl ether derivative of paclitaxel that displays potency superior to paclitaxel against tumor cells in culture and human tumor xenografts. It also inhibits the growth of paclitaxel-resistant human tumor cell lines with multidrug resistance mediated by either P-glycoprotein or mutated tubulin. Given the known synergy between taxanes and cisplatin in vitro and their clinical activity in combination, we performed a Phase I trial of BMS-184476 as a 1-h i.v. infusion followed by cisplatin every 21 days. Twenty-seven patients with a variety of solid tumors and good performance status received 116 cycles of therapy at BMS-184476 doses of 40-60 mg/m(2) together with cisplatin at 75 mg/m(2). The early observation of hypersensitivity reactions required prophylactic premedication in all patients. At the planned highest dose of BMS-184476 (60 mg/m(2)) and cisplatin (75 mg/m(2)), we observed dose-limiting toxicity in the form of neutropenia and diarrhea. Also at this level, five patients experienced grade 3 or worse nausea and vomiting. Aggressive prophylactic treatment eliminated the gastrointestinal toxicity. Mild to moderate peripheral neuropathy was infrequent, as was alopecia. Patient benefits included three partial responses in patients with mesothelioma, esophageal cancer, and head and neck cancer, and two additional minor responses. Plasma pharmacokinetic data are available for 23 patients treated at 40-60 mg/m(2). The mean maximum plasma concentrations and areas under the curves increased in a dose-related manner. The pharmacokinetics of BMS-184476 appeared independent of dose. The mean (+/- SE) values for clearance, volume of distribution at steady state, and the apparent terminal half-lives of the three dose groups during cycle 1 were 243 +/- 5 ml/min/m(2), 423 +/- 58 l/m(2), and 32.2 +/- 4.5 h, respectively. BMS-184476 60 at mg/m(2) with cisplatin at 75 mg/m(2) with appropriate supportive therapy is the dose recommended for further evaluation.
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PMID:Phase I and pharmacokinetic trial of the novel taxane BMS-184476 administered as a 1-hour intravenous infusion in combination with cisplatin every 21 days. 1461 2

Glucocorticoids are often used in veterinary cancer patients because of their anti-inflammatory actions, appetite-stimulating effects, ability to decrease nausea and vomiting associated with some chemotherapy agents, and, in some instances, for their cytotoxic actions on susceptible tumour cells. Veterinary oncologists may not consider the possibility that the use of glucocorticoids may adversely affect response to chemotherapy. There is evidence that glucocorticoids can up-regulate the expression of multidrug resistance genes in some tissues. Whether or not glucocorticoid-induced expression of multidrug resistance proteins occurs in tumour cells is not presently known. The purpose of this study was to determine if dexamethasone induces P-glycoprotein (P-gp) or multidrug resistance-related protein 1 (MRP1) in tumour cell lines. A canine osteosarcoma cell line (OS2.4) and a human myeloid leukaemia cell line 60 (HL60) were treated in culture with dexamethasone. The presence of a glucocorticoid receptor was confirmed in both cell lines by reverse-transcriptase polymerase chain reaction. Western blots for P-gp and MRP1 expression were performed on vehicle-treated and dexamethasone-treated cells. Sensitivity towards several chemotherapeutic drugs (cisplatin (cis-diamminedichloroplatinum), doxorubicin, methotrexate and vincristine) was determined by 3-(4,5-dimthylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. While dexamethasone treatment of OS2.4 cells increased the resistance to cisplatin and methotrexate, an increase in P-gp or MRP1 expression was not observed. Dexamethasone-treated HL60 cells did not develop chemoresistance and did not show increased expression of P-gp or MRP1.
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PMID:Dexamethasone treatment of a canine, but not human, tumour cell line increases chemoresistance independent of P-glycoprotein and multidrug resistance-related protein expression. 1937 18

Multidrug resistance (MDR) in cancer cells is often caused by the high expression of the plasma membrane drug transporter P-glycoprotein (Pgp) associated with an elevated intracellular glutathione (GSH) content in various human tumors. Several chemosensitizers reverse MDR but have significant toxicities. Antiemetic medications are often used for controlling chemotherapy-induced nausea and vomiting in cancer patient. In this in vitro study we investigated if the effects of two common antiemetic drugs such as dimenhydrinate (dime) and ondansentron (onda) and a natural compound (6)-gingerol (ginger), the active principle of ginger root, interfere on Pgp activity and intracellular GSH content in order to evaluate their potential use as chemosensitizing agents in anticancer chemotherapy. The human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx5) that overexpress Pgp, were treated with each antiemetic alone (1, 10 and 20 microM) or in combination with different doxo concentrations (2, 4, and 8 microM). We measured the intracellular accumulation and cytotoxicity of doxo (MTT assay), the cellular GSH content (GSH assay) and ROS production (DFC-DA assay), in comparison with verapamil (Ver), a specific inhibitor for Pgp, used as reference molecule. We found that exposure at 2, 4 and 8 microM doxo concentrations in the presence of dime, onda and ginger enhanced significantly doxo accumulation and cytotoxicity on resistant MES-SA/Dx5 cells when compared with doxo alone. Moreover, treatment with ginger (20 microM) increased cellular GSH content (greater than 10 percent) in resistant cells, while ROS production remained below the control values for all antiemetic compounds at all concentrations. These findings provide the rationale for innovative clinical trials of antiemetics or their derivatives as a new potential generation of chemosensitizers to improve effectiveness of the anticancer drugs in MDR human tumours.
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PMID:Modulation of multidrug resistance P-glycoprotein activity by antiemetic compounds in human doxorubicin-resistant sarcoma cells (MES-SA/Dx-5): implications on cancer therapy. 2438 84

Rolapitant is a selective and long-acting neurokinin-1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting in adults. Four open-label phase 1 studies evaluated the safety and drug-drug interactions of a single dose of rolapitant given intravenously (166.5 mg) or orally (180 mg) with oral digoxin (0.5 mg) or sulfasalazine (500 mg), probe substrates for the P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. Administration of intravenous rolapitant with the substrates did not result in clinically significant effects on digoxin and sulfasalazine pharmacokinetics. In contrast, peak concentration and area under the curve for last quantifiable plasma concentrations increased by 71% (geometric mean ratio [GMR], 1.71; 90% confidence interval [CI], 1.49-1.95) and 30% (GMR, 1.30; 90%CI, 1.19-1.42), respectively, when rolapitant was coadministered orally with digoxin compared with digoxin alone; they increased by 140% (GMR, 2.40; 90%CI, 2.02-2.86) and 127% (GMR, 2.27; 90%CI, 1.94-2.65), respectively, when rolapitant was given orally with sulfasalazine compared with sulfasalazine alone. Adverse events were mild to moderate in severity in the absence or presence of rolapitant. There were no abnormal clinical laboratory or electrocardiogram findings. Thus, whether administered orally or intravenously, rolapitant was safe and well tolerated. Patients taking oral rolapitant with P-gp and BCRP substrates with a narrow therapeutic index should be monitored for potential adverse events; although increased plasma concentrations of these substrates may raise the risk of toxicity, they are not contraindicated.
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PMID:Effects of Rolapitant Administered Intravenously or Orally on the Pharmacokinetics of Digoxin (P-glycoprotein Substrate) and Sulfasalazine (Breast Cancer Resistance Protein Substrate) in Healthy Volunteers. 2890 58

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