Effects of total body irradiation followed by bone marrow transplantation on the disposition kinetics of methotrexate in the rat

Abstract

The effects of total body irradiation followed by bone marrow transplantation on the disposition kinetics of intravenously-administered methotrexate have been studied in the Wistar-Furth rat. Eight test animals received total body irradiation (1000 rads) followed by intravenous administration of 3 X 10(8) bone marrow cells per kg body weight. Eight control animals were sham-irradiated and received an equal volume of blank suspension medium. One day after these treatments each rat received methotrexate (25 mg/kg) by rapid intravenous injection and serial blood samples were obtained over a 3 hour period. Serum methotrexate concentrations were measured by high performance liquid chromatography and pharmacokinetic parameters were calculated after NONLIN analysis of data. No significant differences were observed in total body clearances of test and control animals. As methotrexate in the rat is cleared predominantly by renal excretion of unchanged drug, these findings suggest that this process is not affected by radiation. Significantly larger volumes of distribution were observed in test animals. Increased extent of distribution in irradiated animals could be a result of a radiation-induced increase in membrane permeability and/or increased blood flow to irradiated areas. Future studies should assess the clinical significance of such findings.