Dose-dependent pharmacokinetics of probenecid in the rat.
The basic pharmacokinetics of probenecid was studied by administration of three different i.v. bolus doses (50, 75, and 100 mg kg-1) to rats. The protein binding of probenecid in pooled rat serum was estimated by equilibrium dialysis. The unbound fraction was found to increase non-linearly with increasing total concentration, yielding a maximum free fraction of 49 per cent. The plasma concentration data obtained were described by a two-compartment model with Michaelis-Menten elimination. The maximal rate of elimination (Vm) remained unchanged between different doses irrespective of whether it was calculated in total or free concentrations (mean 187.2 +/- 8.3 (SD) microgram min-1). The Michaelis-Menten constant (Km) decreased slightly with increasing dose, while the unbound Michaelis-Menten constant (Km,u) did not change between the doses (mean 37.1 +/- 1.3 (SD) microgram ml-1). The volume of distribution of the central compartment (Vc) did not alter when the dose was increased from 50 to 100 mg kg-1 (mean 56.5 +/- 4.3 (SD) ml), but the unbound volume of distribution of the central compartment (Vc,u) decreased from 186.5 +/- 15.6 (SD) to 89.8 +/- 6.9 (SD) ml, which is in accordance with the reduction to be expected for drugs that only distribute in the extracellular fluid.
Emanuelsson
B M
BM
Department of Biopharmaceutics and Pharmacokinetics, Uppsala University, Sweden.
Paalzow
L K
LK
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D011339:Probenecid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats
D001798:Blood Proteins; D011339:Probenecid