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)

Cyclosporin A (CsA, Sandimmune) is known to reverse P-glycoprotein (P-gp170)-mediated multidrug resistance as efficiently as other prototype compounds of resistance modifiers. The immunosuppressive activity and nephrotoxicity of CsA, however, may limit its clinical use. PSC-833, a new cyclosporine, exerts a similar resistance-modifying activity but lacks toxicity or immunosuppressive activity. We have tested its potency in vitro and in vivo on the L1210 leukemia cell line transfected with a full-length cDNA copy of the human mdr I gene, which showed a stable 30-fold resistance towards adriamycin as compared to the parental cell line. In vitro growth of the transfected cell was unchanged. In vivo growth was less aggressive; the survival time of inoculated mice was prolonged. In vitro, PSC-833 was at least as potent as CsA or verapamil in reversing multidrug resistance. In vivo, the drug-resistant L1210 leukemia was completely unresponsive to i.v. monotherapy with adriamycin at its maximum tolerated dose (MTD). PSC-833 enhanced the activity and toxicity of adriamycin. The MTD of adriamycin was about 3 times lower than when given alone. On this basis, the MTD of i.v. adriamycin in combination with oral PSC-833 successfully overcame refractoriness to treatment. Survival times of the mice were considerably prolonged and even some cures of leukemic mice occurred.
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PMID:SDZ PSC 833, a non-immunosuppressive cyclosporine: its potency in overcoming P-glycoprotein-mediated multidrug resistance of murine leukemia. 134 37

The new nonimmunosuppressive cyclosporin analogue, SDZ PSC 833, is a very potent multidrug-resistance modifier. In vitro, it was shown to be at least 10-fold more active than cyclosporin A (Sandimmune), itself more active than verapamil, on most P-glycoprotein-expressing multidrug-resistant (MDR) tumor cell lines. In vivo, SDZ PSC 833 was tested in a few protocols of combined therapy with either Vinca alkaloids or doxorubicin as anticancer drugs, using the homologous tumor-host system (P388 cells of DBA/2 origin grafted into DBA/2 or B6D2F1 mice). Although these MDR-P388 tumor cells belong to a highly resistant variant that in vitro required about 150-fold more anticancer drug for 50% cell growth inhibition than the parental P388 cells, significant prolongation of survival times of the MDR-P388 tumor-bearing mice was obtained when treated with a combination of SDZ PSC 833 p.o. were otherwise ineffective doses of anticancer drugs given i.p. This chemosensitizing effect of SDZ PSC 833 was dose-dependent and was most effective in a protocol combining administration of SDZ PSC 833 p.o. 4 h before a doxorubicin i.p. injection: in comparison with the survival of MDR-P388 tumor-bearing mice treated with the anticancer drug alone, the pretreatment with SDZ PSC 833 at 25 and 50 mg/kg gave 2- to 3-fold increases of survival times. Since the MDR-P388 tumor cells used in our studies belong to a highly resistant variant, with a much higher degree of drug resistance than the one known to occur in cancer patients, SDZ PSC 833 appears to be a very promising chemosensitizer.
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PMID:In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. 167 13

Cyclosporin A (Sandimmune) rapidly induced an increase in daunorubicin accumulation in multidrug-resistant human ovarian carcinoma cells (2780AD) and was more potent than verapamil. Steady-state 3H-cyclosporin A accumulation at 37 degrees C in 2780AD cells was 60-70% of that in the sensitive A2780 cells. A rapid increase of ATP consumption and lactate production was induced in 2780AD cells by verapamil, but not by cyclosporin A. These results suggest that the interactions of cyclosporin A and verapamil with P-glycoprotein, which leads to inhibition of drug transport, have a different mechanistic basis.
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PMID:Cyclosporin A and verapamil have different effects on energy metabolism in multidrug-resistant tumour cells. 239 Apr 89

Multidrug resistance (MDR) is considered to be an important impediment to the effective treatment of cancer. P-glycoprotein, the drug efflux pump that mediates this resistance, can be inhibited by a wide variety of pharmacological agents, resulting in the circumvention of the MDR phenotype. SDZ PSC 833 ([3'-keto-Bmt1]-Val2]-cyclosporine), a nonimmunosuppressive cyclosporine D derivative, was identified to be a potent MDR modulator (Gaveriaux et al. J. Cell Pharmacol. 2:225-234; 1991). In this study, the interactions of P-glycoprotein with two cyclosporine derivatives, SDZ PSC 833 and cyclosporine A (CsA, Sandimmune), were analyzed. SDZ PSC 833 enhanced the sensitivity of the MDR cells to anticancer drugs by increasing the accumulation and inhibiting the efflux of cytotoxic agents from resistant cells more efficiently than CsA. The two cyclosporine analogs competed with the labeling of P-glycoprotein by a photoactive cyclosporine derivative. In addition, membrane vesicles derived from resistant cells bound SDZ PSC 833. However, CsA was transported by P-glycoprotein, whereas SDZ PSC 833 was not actively transported. This resulted in a prolonged inhibitory effect by SDZ PSC 833. The studies suggest that the binding of SDZ PSC 833 to P-glycoprotein in the absence of its transport from MDR cells mediated its high potency as an MDR reversing agent. In addition, the comparison of the two cyclosporine analogs indicated that limited chemical modifications of MDR reversing agents can affect their potential to inhibit P-glycoprotein function.
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PMID:Analysis of the interactions of SDZ PSC 833 ([3'-keto-Bmt1]-Val2]-Cyclosporine), a multidrug resistance modulator, with P-glycoprotein. 870 77

Cyclosporin, an immunosuppressant with a narrow therapeutic window, is a substrate for both CYP3A4 and P-glycoprotein (Pgp). Quercetin is an inhibitor of CYP3A4 and a modulator of Pgp. This study aimed to measure the effect of quercetin on the absorption and disposition of cyclosporin in pigs and rats. Cyclosporin (Sandimmune, 10 mg/kg) was orally administered with and without a concomitant dose of quercetin (50 mg/kg) to pigs and rats. Cyclosporin concentrations in blood samples were determined by a specific monoclonal fluorescence polarization immunoassay. The pharmacokinetic parameters were calculated by noncompartmental analysis using WINNONLIN. A paired Student's t-test was conducted for statistical comparison. A study using the everted intestinal sac was carried out to evaluate the effect of quercetin on the function of intestinal Pgp. The coadministration of quercetin significantly decreased cyclosporin AUC(0-3) (area under the concentration-time curve from time zero to 3 h) by 56% and AUC(0-t) (area under the concentration-time curve from time zero to the last point) by 43% in pigs and rats, respectively, indicating that the coadministration of quercetin significantly decreased cyclosporin oral bioavailability. However, the inverted sac study showed that quercetin significantly inhibited the function of intestinal Pgp. It is suggested that concurrent use of quercetin or quercetin-containing dietary supplement or herbs with cyclosporin or other medications whose absorption and metabolism are mediated by Pgp and/or CYP3A4 should require close monitoring.
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PMID:Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats. 1242 82

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

Quercetin and rutin are popular flavonoids in plant foods, herbs, and dietary supplements. Cyclosporine (CSP), an immunosuppressant with a narrow therapeutic window, is a substrate of P-glycoprotein (P-gp) and cytochrome P-450 3A4 (CYP3A4). This study investigated the effects of quercetin and rutin on CSP pharmacokinetics from Neoral and relevant mechanisms. Rats were orally administered Neoral with and without quercetin or rutin. The blood CSP concentration was assayed by a specific monoclonal fluorescence polarization immunoassay. The results showed that quercetin and rutin significantly decreased the C(max) of CSP by 67.8 and 63.2% and reduced the AUC(0-540) by 43.3 and 57.2%, respectively. The in vitro studies indicated that the quercetin and rutin induced the functions of P-gp and CYP3A4. In conclusion, quercetin and rutin decreased the bioavailability of CSP through activating P-gp and CYP3A. Transplant patients treated with Neoral should avoid concurrent consumption of quercetin or rutin to minimize the risk of allograft rejection.
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PMID:Quercetin and rutin reduced the bioavailability of cyclosporine from Neoral, an immunosuppressant, through activating P-glycoprotein and CYP 3A4. 2146 23