Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.1 (Mg2+-ATPase)
 1,484 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By sequestering cytosolic calcineurin into a molecular complex with cyclophilin and its consequent T-cell dysfunction, some cyclosporins, such as CsA and FR901459 ([Thr2-Leu5-Leu10]-CsA), display potent immunosuppressive activity. Independently on this property, cyclosporins may display one or more other biological activities mediated by interaction with cell surface glycoproteins. Several cyclosporins inhibit the function of human MDRI-encoded P-glycoprotein (Pgp), a flippase known to cause cancer multidrug resistance, but also expressed by some normal immunocompetent cells and by normal epithelial cells which control drug bioavailability in vivo. CsA is known to be a potent Pgp inhibitor with a 3.2 microM IC50 in an assay where the most potent derivative SDZ PSC 833 gives a 0.49 microM IC50. FR901459 is now shown to be a good Pgp inhibitor, being 2-fold weaker only (IC50 of 6 microM) than CsA. Some cyclosporins may also inhibit the function of the human FPR1-encoded formyl peptide receptor (FPR), a chemotactic receptor whose absence is known to impair antibacterial immunity. Yet this inhibition is very weak for all, but one of them, CsH, whose 0.15 micro/M IC50 makes it a much more potent FPR inhibitor than CsA (IC50 >10 microM in the same assay). FR901459 is now shown to be a very potent inhibitor of FPR function (IC50 of 0.6 microM). Since CsH shows little Pgp-inhibitory activity and has no known immunosuppressive activity, FR901459 displays a unique pharmacological profile: like CsA, it inhibits T-cell function; less than CsA, it can inhibit Pgp function on selected leukocyte subsets and on epithelial barriers known to control drug bioavailability; however, much more efficiently than CsA, it can inhibit the FPR function, a receptor involved in some leukocytic inflammatory responses to chemotactic peptides.
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PMID:The potent immunosuppressive cyclosporin FR901459 inhibits the human P-glycoprotein and formyl peptide receptor functions. 1090 15

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