EFFECT OF SDZ PSC-833 ([3'-KETO-BMT(1)]-[VAL(2)]-CYCLOSPORINE) ON SERUM-PROTEIN BINDING AND DISTRIBUTION TO BLOOD-CELLS OF DOXORUBICIN, VINCRISTINE AND ETOPOSIDE IN-VITRO

SDZ PSC 833 ([3'-keto-Bmt(1)]-[Val(2)]-cyclosporin) is a P-glycoprotei n-media ted multidrug resistance modulator currently undergoing clinic al trials. SDZ PSC 833 modulates not only antitumor activity but also tissue distribution of doxorubicin in mice, Since protein binding in p lasma/serum and distribution to blood cells are important factors affe cting the tissue distribution and excretion of drugs, we investigated the effect of SDZ PSC 833 on serum protein binding and distribution to blood cells of doxorubicin, vincristine and etoposide in vitro. Unbou nd fractions in serum and tractions distributed to blood cells of eith er [C-14]doxorubicin, [H-3]vincristine or [H-3]etoposide were determin ed using serum and blood obtained from mice and healthy volunteers. Ef fects of SDZ PSC 833 at 3 mu g/ml, which was an achievable concentrati on in a clinical trial of SDZ PSC 833, on protein binding and distribu tion of the drugs to blood cells were negligible in mouse and human bl ood in vitro. The absence of interaction between PSC 833 and the antic ancer drugs in protein binding and distribution to blood cells suggest ed the existence of other mechanisms, Possible interactions are specul ated to be inhibition of P-glycoprotein function contributing to drug excretion end tissue distribution and inhibition of drug metabolism me diated by cytochrome P450 3A.