EFFECT OF ETOPOSIDE ON THE PHARMACOKINETICS OF METHOTREXATE IN-VIVO

The effect of etoposide on the pharmakokinetics of methotrexate (MTX) was examined in vivo, High-dose (5 g/m(2)/24 h) MTX therapy was combin ed with two etoposide (100 mg/m(2)/1 h) infusions as a part of the med ulloblastoma protocol developed in our department. Vepesid therapy was administered in two different schedules. The first group of patients received etoposide immediately before and at the end (24 h) of MTX tre atment, The second group was treated with etoposide at 24 and at 48 h after starting MTX infusion. In this latter group both treatment-relat ed grade III and grade IV toxicity developed more frequently than in t he first group (58.6 versus 29.2%, for grade 3 toxicity p=0.019, for g rade 4 toxic signs p=0.040, respectively). We observed that after the second dose of etoposide given at 48 h (second group) both total and u nbound serum MTX levels (determined by high-performance liquid chromat ography) were elevated by 53-109 and 26-65%, respectively, by the thir d hour after completion of Vepesid infusion. This effect was detectabl e for 6 h. AII the liver and kidney functions of the patients were wit hin the normal range. These results suggest the possibility of partial recirculation of extra/intracellular MTX into the blood after etoposi de administration, Based on these results, the therapeutic protocol ha s been modified, and Vepesid is given prior to and at the end (24 h) o f high-dose MTX treatment. Under these conditions only a slight decrea se of MTX elimination has been detected between 25 and 28 h, These res ults emphasize the role of possible schedule-dependent interactions of cytostatic drugs. [(C) 1998 Lippincott Williams & Wilkins.].