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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

The effects of probenecid upon the individual components of indomethacin elimination.

The effects of probenecid upon plasma profiles for indomethacin and upon the individual components of total plasma clearance have been evaluated in dogs, monkeys and rats. These three species cover the wide spectrum of species differences with respect to the relative contribution of renal, biliary and metabolic clearances to elimination of indomethacin. In dogs, in which biliary clearance is the major component of elimination, probenecid raised incremental values for area under the plasma curve [AUC] greater than 2-fold and completely obliterated the normal portal: peripheral gradient of drug after i.v. dosage. Biliary clearance, measured directly, was inhibited 70%. In rats, in which metabolic clearance is predominant, probenecid had no significant effect upon plasma clearance. In rhesus and spider monkeys, in which renal, metabolic and biliary clearances are all significant, as in man, areas under the plasma curve for indomethacin were more than doubled by probenecid, concomitant with profound depressions of both renal and biliary clearances. If plasma levels are a valid index of pharmacological availabiltiy and amount of drug secreted in bile a correlate of intestinal irritation, probenecid increases therapeutic ratio with respect to intestinal toxicity ca. 5-fold in spider monkeys and 10-fold in rhesus monkeys.[1]


  1. The effects of probenecid upon the individual components of indomethacin elimination. Duggan, D.E., Hooke, K.F., White, S.D., Noll, R.M., Stevenson, C.R. J. Pharmacol. Exp. Ther. (1977) [Pubmed]
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