Urate excretion: drug interactions.

A derivative of probenecid, 2-nitroprobenecid, was studied in chimpanzees and Cebus monkeys. The uricosuria induced by the drug could be diminished by the infusion of p-aminohippurate (chimpanzee) or hippurate (monkey). Both hippurates inhibited the secretion of the drug and it is likely that the diminished response was the result of decreased access of 2-nitroprobenecid to its site of action. In contrast, pyrazinoate diminished the response to 2-nitroprobenecid without disturbing its renal disposition (both species). This action of pyrazinoate is attributed to its ability to inhibit the secretory flux of urate. The effect of pyrazinoate is diminished at high levels of 2-nitroprobenecid, i.e., it appears as if pyrazinoate causes a shift to the right of the concentration-response curve of 2-nitroprobenecid. A mathematical model is developed which seems to explain this apparent shift in the concentration-response curve. This model requires that the transepithelial fluxes for urate be very large. In the chimpanzee the action of salicylate resembles that of pyrazinoate but it is less prominent.