Effect of SDZ PSC 833 ([3'-keto-Bmt1]-[Val2]-cyclosporin) on serum protein binding and distribution to blood cells of doxorubicin, vincristine and etoposide in vitro.
SDZ PSC 833 ([3'-keto-Bmt1]-[Val2]-cyclosporin) is a P-glycoprotein-mediated multidrug resistance modulator currently undergoing clinical trials. SDZ PSC 833 modulates not only antitumor activity but also tissue distribution of doxorubicin in mice. Since protein binding in plasma/serum and distribution to blood cells are important factors affecting 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. Unbound fractions in serum and fractions distributed to blood cells of either [14C]doxorubicin, [3H]vincristine or [3H]etoposide were determined using serum and blood obtained from mice and healthy volunteers. Effects of SDZ PSC 833 at 3 microg/ml, which was an achievable concentration in a clinical trial of SDZ PSC 833, on protein binding and distribution of the drugs to blood cells were negligible in mouse and human blood in vitro. The absence of interaction between PSC 833 and the anticancer drugs in protein binding and distribution to blood cells suggested the existence of other mechanisms. Possible interactions are speculated to be inhibition of P-glycoprotein function contributing to drug excretion and tissue distribution and inhibition of drug metabolism mediated by cytochrome P450 3A.
Watanabe
T
T
Sandoz Tsukuba Research Institute, Sandoz Pharmaceuticals, Ltd, Tsukuba-shi, Ibaraki, Japan.
Iwasaki
M
M
Todaka
T
T
Morikawa
H
H
Ohtawa
M
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000097:blood*; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood*; D001773:Blood Cells / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism*; D003524:Cyclosporins / Q000494:pharmacology*; D004317:Doxorubicin / Q000097:blood*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D005047:Etoposide / Q000097:blood*; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D011485:Protein Binding / Q000187:drug effects; D014018:Tissue Distribution; D014750:Vincristine / Q000097:blood*
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D001798:Blood Proteins; D003524:Cyclosporins; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; C070272:valspodar