Influence of schedule of administration on methotrexate penetration in brain tumours

The influence of the administration schedule (intravenous (i.v.) bolus vers us i.v. infusion) on the pharmacokinetics of methotrexate (MTX) in plasma a nd extracellular fluid (ECF) of a brain C6-glioma was investigated in rats. MTX concentrations were determined by high performance liquid chromatograp hy (HPLC)-ultraviolet radiation(UV). MTX (50 mg/kg) was administered by i.v . bolus or i.v. infusion (4 h). Concentration-time profiles were fitted to a two-compartment open model. Maximum MTX concentrations ranged between 178 and 294 mu g/ml (i.v. bolus), and between 11 and 24 mu g/ml (i.v. infusion ) in plasma. MTX rapidly entered the tumour tissue although its concentrati ons in the ECF were much lower than those observed in plasma for both modes of administration. In spite of an important interindividual variability, A UC(ECF) was approximately 5-fold higher and mean MTX penetration in tumour ECF (AUC(ECF)/AUC(Plasma)) was approximately 3-fold higher after i.v. bolus than after i.v. infusion administration. These results indicate that i.v. bolus administration schedules promote MTX delivery in brain tumour tissue. (C) 2000 Elsevier Science Ltd. All rights reserved.