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 (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.

A Species Difference in the Transport Activities of H2Receptor Antagonists by Rat and Human Renal Organic Anion and Cation Transporters

“…Boom and Russel (1993) demonstrated that the major fraction of cimetidine uptake (approximately 50%) by freshly isolated rat proximal tubular cells was inhibited by TEA, suggesting a major role of OCTs. Probenecid was only a weak inhibitor with an IC 50 value (700 M) greater than the plasma unbound concentration employed in drug-drug interaction studies (Emanuelsson and Paalzow, 1988;Lin et al, 1988). Indeed, probenecid had a weak effect against OCTs.…”

Probenecid Pre-treatment Downregulates the Kidney Cl-/HCO3- Exchanger (Pendrin) and Potentiates Hydrochlorothiazide-Induced Diuresis

“…The time lines for experimental protocols are described in Figure 1 . The dosing for probenecid was selected based on published literature in rodents ( Emanuelsson and Paalzow, 1988 ; Hesselink et al, 1999 ). Male Sprague Dawley rats were treated under 3 different protocols: (1) HCTZ (40 mg/kg/day for 4 days), (2) probenecid (250 mg/kg/day for 10 days), and (3) primed with probenecid (250 mg/kg/day) for 6 days followed by probenecid (250 mg/kg/day) and HCTZ (40 mg/kg/day) for 4 additional days.…”

Zidovudine Transport within the Rabbit Brain during Intracerebroventricular Administration and the Effect of Probenecid

“…11 Ventricular CSF was assumed to be well-mixed, based on rapid turnover of CSF. 17,20 Assuming a ventricular CSF volume of 0.51 mL/kg, 17 the elimination rate constant or halflife from CSF can be calculated from estimated values of CL f . The elimination half-lives of AZT (mean ( SD) from CSF are 12.4 ( 4.8, 13.6 ( 2.1, and 40.2 ( 8.5 min at dosing rates of 0.01, 0.1, and 1 mg/h kg, respectively.…”

“…The pharmacokinetics of PBD have been studied in various animals [20][21][22][23] and in human. 24 In the present study, the CSF to plasma concentration ratio (0.2) of this agent was much smaller than unity.…”