Probenecid organic cation transport

The nephrotoxicity of dsplatin is reduced in humans [132], mice [133] and dogs [134] by co-admin-istration of probenecid, suggesting that cisplatin is transported by the PAH transport system. It has been proposed that platinum, hke other nephrotoxic metal ions such as mercury and potassium dichromate, are taken up by tubular cells as sulphydryl conjugate through a probenecid-sensitive pathway [133]. However, cisplatin might also be transported by the organic cation transport system, since quinidine, cimetidine and ranitidine inhibited its net secretion flux in the dog kidney [134]. 

The OAT family of transporters can be inhibited by probenecid. If a substrate of this family of transporters, such as penicillin, is administered concomitantly with probenecid, the dmg can have decreased renal secretion, with a resulting increase in the plasma penicillin concentration. Cimetidine is an inhibitor of members of the OAT, organic cation transporter (OCT) and OATP families of transporters This inhibition has been shown to result in a decrease in the renal excretion of substrates such as procainamide and levofloxacin, resulting in increased plasma concentrations of these dmgs. 

Tubular secretion The active secretory systems can rapidly remove the protein-bound drugs from the blood and transport them into tubular fluid as the drugs that are bound to proteins are not readily available for excretion by filtration. The drugs known to be secreted by organic anion secretory system (i.e. strong acids) are salicylates, chlorothiazide, probenecid, penicillin etc. and cation (i.e. bases) includes catecholamines, choline, histamine, hexamethonium, morphine etc. 

Certain molecules, such as p-aminohippuric acid (Fig. 3.18), a metabolite of p-aminobenzoic acid are actively transported from the bloodstream into the tubules by a specific anion transport system. Organic anions and cations appear to be transported by separate transport systems located on the proximal convoluted tubule. Active transport is an energy-requiring process and therefore may be inhibited by metabolic inhibitors, and there may be competitive inhibition between endogenous and foreign compounds. For example, the competitive inhibition of the active excretion of uric acid by compounds such as probenecid may precipitate gout. 

Probenecid markedly increased the AUC of the active metabolite of oseltamivir, but because of the large safety margin of oseltamivir, this increase is not considered to be clinically relevant. " Oseltamivir did not alter amoxicillin pharmacokinetics, and is therefore unlikely to interact with other renally secreted organic acids. Other drugs that are involved in the active anionic tubular secretion mechanism are also unlikely to interact. Cimetidine does not interact with oseltamivir, and other drugs that are inhibitors of the renal cationic secretion transport process are unlikely to interact. ... 

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