Application of effect-compartment model to bumetanide-indomethacin interaction in dogs

Analyses of bumetanide's dose-response relationship have been complicated by the hysteresis observed between the drug's urinary excretion rate and its sodium excretion. This apparent time lag reflects the disequilibrium between the urine concentration and effect compartment (biophase) which occurs during the early distribution phase. In the present article, an expanded pharmacodynamic model has been introduced in which the hypothetical effect compartment is linked, by a first-order process (Kue), to the urine compartment. Drug dissipation from the effect compartment occurs by means of the first-order rate constant, Keo. This representation accommodates bumetanide's luminal site of action in the kidney tubule as well as the drug's temporal component. Application of this model to the bumetanide-indomethacin interaction in dogs is examined.