title: Saturable kinetics of intravenous chlorothiazide in the rhesus monkey.
abstract: 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.
mesh_terms: D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002740:Chlorothiazide / Q000008:administration & dosage / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007678:Kidney Glomerulus / Q000378:metabolism; D007700:Kinetics; D008253:Macaca mulatta; D011339:Probenecid / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D001798:Blood Proteins; D002740:Chlorothiazide; D011339:Probenecid