Kinetics of d-tubocurarine disposition and pharmacologic response in rats

After bolus intravenous dosing of d-tubocurarine (d-TC) to rats, the twitch heights of the tibialis anterior muscle indirectly stimulated were followed, and its decrease was defined as pharmacologic response of d-TC. The relation between dose and response intensity was found to be well described with Hill's equation. According to a theory proposed by Smolen, Hill's equation was also applicable to the biophase d-TC concentration-response relation; the time courses of the relative biophase d-TC concentration indicated linear kinetics with dose levels less than or equal to 0.15 mg/kg and the occurrence of dose-dependent disposition with 0.30 mg/kg. After bolus i.v. dosing of 3H-d-TC, plasma d-TC concentration obeyed a dose-independent two compartment model with doses less than or equal to 0.15 mg/kg, but not with 0.30 mg/kg. This finding matched the above estimated with pharmacologic data. The active metabolite was not found in plasma and urine. The extent of d-TC plasma protein binding was independent of the wide range of plasma levels and its mean (+/- SD) value was 30.5 (+/- 3.8). Plasma d-TC levels and pharmacologic response intensity were well correlated by Hill's equation and a three compartment model (the general two and the biophase compartments) in the dose range less than or equal to 0.15 mg/kg.