Dose-Dependent Kinetics of Probenecid in Rhesus Monkeys &amp;ndash; Infusion Studies

Chiang, C. Nora; Benet, Leslie Z.

doi:10.1159/000137960

Cited by 7 publications

(3 citation statements)

References 4 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Wei

Sawchuk³

1997

Journal of Pharmaceutical Sciences

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The elimination of zidovudine (AZT) from cerebrospinal fluid (CSF), its distribution from CSF to brain tissue, and its transport from brain extracellular fluid (ECF) to plasma were studied during intracerebroventricular (i.c.v.) infusion in unanesthetized rabbits. The effect of probenecid (PBD) on these transport processes was also studied. The concentration of AZT in brain ECF was measured by microdialysis with retrodialysis calibration for in vivo recovery. Plasma and CSF were sampled and analyzed for AZT and PBD using HPLC. The elimination of AZT from CSF showed nonlinear characteristics as the i.c.v. infusion rate was increased to 1 mg/h kg. The estimated maximum transport capacity and dissociation constant were 3.5 micrograms/min kg and 127 micrograms/mL, respectively. The total linear elimination clearance from CSF was 0.0073 mL/min kg. The spatial distribution of AZT in brain during i.c.v. infusion was simulated using a mathematical model which describes diffusive solute transport in brain ECF and efflux across the blood-brain barrier. This analysis yielded a brain to plasma efflux rate constant of 0.040/min. This parameter and the elimination clearance from CSF decreased significantly by the end of an 8-hour period during which PBD was infused intravenously at a rate of 15 mg/h kg.

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Section: Discussionmentioning

confidence: 99%

“…This may be due in part to plasma protein binding. It has been reported that PBD is more than 80% protein bound in dog, 21 monkey, 23 and human. 24 After correcting this ratio for protein binding, assuming a similar protein binding in rabbit plasma as in other species, the free concentrations of PBD in CSF are similar to those in plasma.…”

Section: Discussionmentioning

confidence: 99%

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

Wang

Wei

Sawchuk³

1997

Journal of Pharmaceutical Sciences

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“…1963;Emanuelsson et al, 1987] and animals [Chiangand Benet, 1982, 1984Emanuelsson and Paalzow. 1980], The metabolism has been studied both in vivo and in vitro [Israili et al, 1972;Guarino et al, 1969;Perei et al, 1970Perei et al, .…”

Section: Discussionmentioning

confidence: 99%

Hepatic and Renal Clearances of Probenecid in the Rat

Emanuelsson

Paalzow²

1989

Pharmacology

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The elimination kinetics of probenecid in the rat was studied by using an in vitro liver perfusion system to estimate its basic elimination and in vivo to estimate its renal excretion by catheterization of the urinary bladder. In the liver perfusion study different amounts of probenecid were added to the perfusion medium yielding different initial concentrations (40, 200 and 400 μg/ml), and 4 different intravenous bolus doses (50, 75, 100 and 200 mg/kg) were administered in vivo to rats in order to evaluate the renal excretion. The results obtained were described by one-compartment models, with Michaelis-Menten elimination by the liver V_m = 67.4 ± 14.0 (SD) μg/min and a slightly decreasing K_m with increasing initial concentrations [from 76.5 ± 9.0 to 53.2 ± (SD) 18.4 μg/ml]. The excretion by the kidney was characterized by a saturable pathway in parallel with first-order elimination, the maximum rate of the active transports T_m = 0.04 ± (SD) 0.09 μg/min, K_m,r =100.3 ± (SD) 12.3 μg/ml and a linear renal clearance of 0.0008 ± (SD) 0.0002 ml/min.

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Dose‐dependent pharmacokinetics of probenecid in the rat

Emanuelsson

Paalzow

1988

Biopharm & Drug Disp

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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.

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Dose-Dependent Kinetics of Probenecid in Rhesus Monkeys – Infusion Studies

Cited by 7 publications

References 4 publications

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

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

Hepatic and Renal Clearances of Probenecid in the Rat

Dose‐dependent pharmacokinetics of probenecid in the rat

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