Serum protein reduction of the enhancement of methotrexate accumulation by vincristine and 4'-demethylepipodophyllotoxin in the Ehrlich ascites tumor cell in vitro.
The Vinca alkaloid vincristine and the epipodophyllotoxin derivative teniposide significantly elevate steady state levels of methotrexate in the Ehrlich ascites tumor cell in vitro. However, the presence of circulating serum proteins compromises this drug-cell interaction. In the presence of bovine serum albumin, elevation of cellular methotrexate levels by vincristine and teniposide in vitro is reduced by 60-70%. In the presence of physiological concentrations of human serum albumin and human serum glycoproteins, the enhancement of cellular methotrexate accumulation by vincristine is reduced by approximately 50% while enhancement of cellular methotrexate accumulation by teniposide is essentially eliminated. These findings may in part explain the observations that vincristine does not alter the cellular pharmacokinetics of methotrexate in vivo and may provide a rationale for the lack of therapeutic synergism between vincristine and methotrexate when the Vinca alkaloid is administered concurrent with or prior to the antifolate compound in the tumor bearing animal. Furthermore these studies indicate the difficulties inherent in attempting to extrapolate from in vitro studies of drug-cell interaction to the intact animal.
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001798:Blood Proteins / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism*; D002478:Cells, Cultured; D008297:Male; D008727:Methotrexate / Q000378:metabolism*; D051379:Mice; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D013713:Teniposide / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology*
D001798:Blood Proteins; D014750:Vincristine; D013713:Teniposide; D011034:Podophyllotoxin; D008727:Methotrexate