Dose‐dependent pharmacokinetics of probenecid in the rat

Abstract

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 (V_m) remained unchanged between different doses irrespective of whether it was calculated in total or free concentrations (mean 187·2±8·3 (SD) μg min⁻¹). The Michaelis‐Menten constant (K_m) decreased slightly with increasing dose, while the unbound Michaelis‐Menten constant (K_{m, u}) did not change between the doses (mean 37·1±1·3 (SD) μg ml⁻¹ ). The volume of distribution of the central compartment (V_{c, u}) 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 (V_{c, 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.