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Dose‐dependent pharmacokinetics of probenecid in the rat
Author(s) -
Emanuelsson BM.,
Paalzow L. K.
Publication year - 1988
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bod.2510090107
Subject(s) - probenecid , pharmacokinetics , chemistry , volume of distribution , free fraction , elimination rate constant , distribution volume , extracellular fluid , michaelis–menten kinetics , bolus (digestion) , distribution (mathematics) , pharmacology , chromatography , medicine , extracellular , biochemistry , enzyme , mathematical analysis , mathematics , enzyme assay
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.