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)

Resistance of cancer cells is the major limitation to the success of chemotherapy. Although many mechanisms of cellular resistance to anticancer drugs have been defined, the best understood of these is multidrug resistance (MDR), caused by the multidrug transporter, P-glycoprotein (P-gp), the product of the MDR1 gene. New drugs developed specifically to inhibit P-gp and modulate MDR, such as valspodar (PSC 833 [Amdray]), are currently undergoing clinical testing. Moreover, agents designed to inhibit other mechanisms of drug resistance are currently in development, and concurrent blockade of multiple mechanisms of resistance appears to be a promising approach. Coadministration of MDR1-related chemotherapeutic drugs with an MDR modulator may enhance the bioavailability of these agents sufficiently to enable oral dosing, which would potentially be more convenient and less toxic.
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PMID:Modulation of multidrug resistance: a paradigm for translational clinical research. 1037 Sep 27

The aim of this multicenter study was to determine whether valspodar (Amdray; code designation, SDZ PSC 833), a potent P-glycoprotein (P-gp) inhibitor, affects the pharmacokinetics of unbound paclitaxel (Cu). Data were obtained from 31 patients with advanced breast cancer. Thirteen patients were treated with paclitaxel alone (3-h infusion at 175 mg/m2) and another 18 received paclitaxel (3-h infusion at 70 mg/m2) in combination with a 21-day cycle of oral valspodar (5 mg/kg given four times a day) starting 1 day before administration of paclitaxel. Serial blood samples were taken in the first course and Cu in plasma determined using equilibrium dialysis with a [G-3H]paclitaxel tracer. The apparent clearance of Cu was not significantly different between the two groups, with mean +/- standard deviation (+/- SD) values of 230 +/- 56.0 and 202 +/- 49.9 L/h/m2 in the absence and presence of valspodar, respectively (P = 0.17). The volume of Cu distribution was slightly larger in the presence of valspodar (1160 +/- 474 vs. 1620 +/- 552 L/m2; P = 0.025), which contributed to a minor difference in the terminal disposition half-life (6.12 +/- 3.42 vs. 8.50 +/- 2.06 h; P = 0.028). These data indicate that (i) valspodar lacks the significant interaction with paclitaxel observed previously with other P-gp modulators, (ii) the majority of the increased toxicity of the combination does not appear to be attributable to increased levels of Cu, and (iii) provide further evidence of the conjecture that the plasma concentration of paclitaxel may not be an appropriate measure to monitor the impact of P-gp inhibition.
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PMID:Effect of valspodar on the pharmacokinetics of unbound paclitaxel. 1457 79

Valspodar (Amdray, SDZ PSC 833) is derived from cyclosporin, but lacks the immunosuppressive and most of the collateral activities of cyclosporin A (CsA, Sandimmune, Neoral); it exhibits an enhanced capacity to chemosensitise tumour cells showing the classical type multiple drug-resistance (MDR) associated with MDR1 P-glycoprotein (Pgp) overexpression. This valspodar-mediated chemosensitisation of MDR tumour cells is reviewed with regard to its mechanism of inhibition on Pgp flippase function, and its potential inhibition of anticancer drug (ACD) metabolisation by CYP3A enzymes is discussed. Potent inhibition of the membranous and cytoplasmic detoxification mechanisms expressed by cells at the absorption and clearance borders in the body by valspodar results in the many pharmacokinetic interactions with other drugs that are substrates of either, or both, Pgp and CYP classes of detoxifying enzyme. In view of the present ability to restrict oral bioavailability of valspodar within a narrow range, and to adapt adequately the chemotherapeutic dosages to achieve their equivalent exposure in the presence or absence of valspodar, current clinical data on its efficacy and safety permit optimism for ongoing Phase III trials. The potential of valspodar to increase exposure or to modulate the biodistribution of other chemotherapeutics, such as HIV protease inhibitors to the brain, is further evoked, as this might become another application of the new drug. This evaluation of valspodar compared to CsA attempts to interpret its mechanisms of action, rather than to serve as a complete and comparative repertoire of all published preclinical and clinical data.
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PMID:Valspodar: current status and perspectives. 1599 33