PHARMACOKINETICS OF DIFFERENT DOSES OF METHOTREXATE AT STEADY-STATE BY IN-SITU MICRODIALYSIS IN A RAT MODEL

We used a microdialysis technique to monitor extracellular methotrexat e (MTX) levels during the steady state in a rodent model. Microdialysi s probes were implanted in the muscle, liver, and kidney of anesthetiz ed male Wistar rats. MTX (18.75-500 mg/kg) was given as a continuous i nfusion through a venous catheter, and blood samples were obtained thr ough a second venous catheter. Heparinized plasma, ultrafiltered plasm a, microdialysis effluent from tissues, and tissue samples (obtained a t the end of experiments) were analyzed for MTX content by high-perfor mance liquid chromatography (HPLC). Steady state was demonstrated in t he blood and tissues from 2 h until the end of the experiments (6 h). Extracellular drug levels in muscle and liver displayed a linear corre lation with doses, whereas kidney levels reached a plateau at an MTX d ose of 150 mg/kg per 6 h. Microdialysis-fluid endpoint levels for musc le, liver, and kidney were positively correlated to the endpoint total tissue levels (r(2) = 0.80, 0.85, and 0.68, respectively). In the kid neys, the maximal relative tissue MTX accumulation was measured at a t otal dose of 75 mg/kg per 6 h. At higher doses, the relative drug sequ estration declined to less than half of the values observed at this do se. This study demonstrates that the microdialysis technique can provi de reproducible data on MTX tissue exposure in an animal model and tha t it offers a means of serial and reproducible monitoring of extracell ular-tissue MTX levels at steady state and over a wide dose range. Pen ding additional studies, microdialysis may be a helpful technique for elucidating the kinetics of drug delivery to both targeted and toxicit y-prone tissues during chemotherapy.