A range of bolus doses of 14C-chlorothiazide and unlabeled
drug (6.7-30 mg/kg) were administered to each of three unanesthetized rhesus monkeys with and without concurrent
probenecid dosing. Plasma up to 4 h and urine up to 24 h were sampled frequently. Apparent terminal plasma half-lives ranged from 18 to 25 min in the absence of
probenecid. No apparent trend was noted for the volume of distribution of the central compartment calculated from estimated plasma concentrations at time zero. For
chlorothiazide studies, an average of 92% of the dose was recovered in urine by 24 hr. Plasma and urinary clearances at low doses were 20 to 50% higher than those found with higher doses. These dose-dependent clearances for
chlorothiazide were found at doses parallel to the most often prescribed clinical doses in humans on a g
chlorothiazide per kg
body weight basis. Clearances in the presence of
probenecid decreased two- to four-fold over those seen without
probenecid. Incremental renal clearances of
chlorothiazide in the studies with and without
probenecid were also evaluated. Curvilinear segments characteristic of dose-dependent kinetics were demonstrated in graphs of urinary excretion rate versus plasma concentrations. Values of Michaelis-Menten constants Vmax and Km were calculated for renal excretion of
chlorothiazide by active transport after intravenous doses in all three monkeys. The contribution of glomerular filtration to
chlorothiazide renal clearance was found to be negligible. Values of the constant KI (the concentration of the
probenecid competitive inhibitor of
chlorothiazide, which double the apparent Km value of
chlorothiazide) were calculated using the previously calculated Vmax and Km values.