REVERSAL ACTIVITY OF CYCLOSPORINE-A AND ITS METABOLITES M1, M17 AND M21 IN MULTIDRUG-RESISTANT CELLS

Cyclosporin A (CSA) is an effective inhibitor of the P-glycoprotein (P -gp) activity and has been shown to modulate multidrug resistance (MDR ) in in vitro experimental models. During degradation of CSA, the meta bolites arising from the parental compound reach high levels in the se rum of patients, and it is not clear whether these metabolites maintai n the reversal activity of the parental compound, like the metabolites of verapamil, In an in vitro experimental model, we compared the reve rsal activity of CSA and 3 CSA metabolites (M1, M17, and M21) in the r ange of concentrations obtained in whole blood during a clinical trial with CSA used as a revertant agent, As experimental model we used LoV o-resistant cells. Our in vitro studies indicated that the metabolic h ydroxylation and demethylation of CSA lead to molecules that greatly d iffer from the parent drug in their reversal activity, In the range of concentration detected in the whole blood of the patients (1-3 mu M), CSA had a significant reversal activity, It decreased the IC50 Of ant ineoplastic drugs involved in MDR(vincristine, taxol, doxorubicin and etoposide) but not the IC50 of platinum or methotrexate. CSA increased intracellular doxorubicin content and inhibited P-gp (3)[H]azidopine photolabeling, Conversely, CSA metabolite concentrations superimposabl e to those observed in the patients (0.5-2.2 mu M) had no sensitizing effects on the cytotoxicity of MDR-related anti-neoplastic drugs, nor did they affect (3)[H]azidopine photolabeling or doxorubicin uptake, T his study demonstrates that, during degradation of CSA, metabolite der ivatives arise that have a very different reversal activity from that of the parental compound. (C) 1997 Wiley-Liss, Inc.