Dose-dependent pharmacokinetics of probenecid in the rat

Biopharm Drug Dispos. Jan-Feb 1988;9(1):59-70. doi: 10.1002/bod.2510090107.

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 (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Proteins / metabolism
  • Injections, Intravenous
  • Kinetics
  • Male
  • Metabolic Clearance Rate
  • Probenecid / administration & dosage
  • Probenecid / blood
  • Probenecid / pharmacokinetics*
  • Protein Binding
  • Rats

Substances

  • Blood Proteins
  • Probenecid