Methotrexate Tissue Distribution: Prediction by a Mathematical Model2

A model system, discussed and developed in detail in previous publications, was used to predict the distribution of 3′,5′-tritiated methotrexate (MTX) in several mammalian species. Data from experimental studies showed the predictive capabilities of this model when its parameters are chosen to account for physiological differences among species. Some awareness of the critical factors explaining the complex plasma concentration history of MTX resulted during the development of this model. Important aspects were: a) liver uptake and biliary secretion; b) gastrointestinal reabsorption and transit; c) kidney clearance. Computer simulations of a wide range of doses and a few schedules are presented. Species differences in drug distribution and in drug toxicity are discussed in terms of these model predictions.