PMID: 3761166Jul 1, 1986Paper

Probenecid disposition by parallel Michaelis-Menten and dose-dependent pseudo-first-order processes

Journal of Pharmaceutical Sciences
J C HoS Melethil

Abstract

Re-evaluation of published data on the urinary excretion of probenecid [4-(dipropylamino)sulfonylbenzoic acid, 1] and its metabolites as a function of orally administered dose has revealed that the elimination process is comprised of five parallel pathways. Excretion of the major metabolite, the acyl glucuronide 2 (35-45% of dose), follows Michaelis-Menten kinetics. The three oxidized metabolites, the mono-N-propyl, carboxylic acid, and secondary alcohol derivatives 3, 4, and 5, respectively, (totaling 30% of dose), each adhere to pseudo-first-order kinetics in which the elimination rate constant, as a result of product inhibition, is a function of the administered dose. Four to 13% of the dose is eliminated unchanged in apparent first-order fashion. A mathematical relationship between elimination half-life and dose, under conditions of product inhibition, is derived. Computer simulation of the elimination process confirms the experimental observation that the fraction of dose excreted in the form of each metabolite remains relatively constant over the dose range of 0.5 to 2 g. This study is believed to represent the first application of parallel Michaelis-Menten and dose-dependent pseudo-first-order processes to drug dispositi...Continue Reading

References

Jun 1, 1976·Journal of Pharmaceutical Sciences·S Melethil, W D Conway
May 1, 1972·Journal of Pharmaceutical Sciences·T Tsuchiya, G Levy
Dec 1, 1970·Life Sciences. Pt. 1: Physiology and Pharmacology·J M PerelP G Dayton
Jan 1, 1983·Drug Metabolism Reviews·P G Dayton, J E Sanders

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Citations

Oct 15, 1993·Pharmacy World & Science : PWS·T B VreeM M Broekman
Oct 16, 1992·Pharmaceutisch Weekblad. Scientific Edition·T B VreeY A Hekster

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