Dose-dependent pharmacokinetics of cimetidine in the rat

The pharmacokinetics of cimetidine were studied in the rat after intraperitoneal administration of 10, 40 and 100 mg/kg. The area under the plasma concentration-time curve increased more than proportionately with dose. The total plasma clearance of cimetidine decreased as the dose increased (4.11 to 2.21 l/h per kg) with a consequent increase in half-life (24.0 to 37.9 min) but no change in volume of distribution (mean 2.31 l/kg). The fraction of dose excreted unchanged increased slightly with dose (0.37 to 0.45), whereas the fraction excreted as the sulphoxide metabolite decreased significantly with increased dose (0.35 to 0.14). Both the renal clearance (1.52 to 0.99 l/h per kg) and the formation clearance of the sulphoxide metabolite (1.45 to 0.30 l/h per kg) decreased with increasing dose. Residual clearance, calculated as the difference between total clearance and the sum of renal and metabolic clearance, did not change with dose (mean 1.08 l/h per kg). The formation clearance of the sulphoxide metabolite became saturated at a lower cimetidine concentration than the renal clearance.