Probenecid

PHARMACOLOGICAL ACTIONS Inhibition of Inorganic Acid Transport

The actions of probenecid are confined largely to inhibition of the transport of organic acids across epithelial barriers. When tubular secretion of a substance is inhibited, its final concentration in the urine is determined by the degree of filtration—which in turn is a function of binding to plasma protein—and by the degree of reabsorption. The significance of each of these factors varies widely with different compounds. Usually, the end result is decreased tubular secretion of the compound, leading to decreased urinary and increased plasma concentration.

Uric acid is the only important endogenous compound whose excretion is known to be increased by probenecid. This results from inhibition of its reabsorption (see above). The uricosuric action of probenecid is blunted by the coadministration of salicylates.

ABSORPTION, FATE, AND EXCRETION

Probenecid is absorbed completely after oral administration. Peak concentrations in plasma are reached in 2-4 hours. The t/2 of the drug in plasma is dose-dependent and varies from <5 hours to >8 hours over the therapeutic range. Between 85% and 95% of the drug is bound to plasma albumin; unbound drug is cleared by glomerular filtration. The majority of the drug is secreted actively by the proximal tubule. The high lipid solubility of the undissociated form results in virtually complete absorption by backdiffusion unless the urine is markedly alkaline. A small amount of probenecid glucuronide appears in the urine. It also is hydroxylated to metabolites that retain their carboxyl function and have uricosuric activity.

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