Inhibition of p-Aminohippurate Transport by Cholegraphic Agents 1

Abstract

Summary and Discussion

These data show that under proper conditions, and at an appropriate dose, the cholecystography agents can inhibit the transport of PAH both in vitro and in vivo. By inference, this suggests that these agents, or their glucuronide conjugates, may participate in the organic acid transport mechanism of the proximal tubule. This has been demonstrated for iophenoxic acid in a separate study (unpublished observations). Definitive experiments on the other oral agents are not available. In the case of iodipamide, its modest inhibition of PAH secretion in the dog can probably not be attributed to its own participation in proximal transort, since Berndt and Mudge (7) could find no evidence for iodipamide secretion in the dog, although it was demonstrable in the rabbit. Using far larger doses, Lindgren (8) has found marked renal hemodynamic responses to this agent.

A major problem posed by these studies is the evaluation of in vivo inhibitory potency. Presumably, either total plasma concentration or the concentration of the free (unbound) drug is the appropriate reference point. Considering iophenoxic acid, for which plasma levels are available, in the first post injection period, at the peak of PAH inhibition, the level of total drug in the plasma was 490 μg/ml, of which 2.9% was free. In the case of probenecid, Beyer et al. (9) found maximal inhibition of PAH secretion at plasma levels of 200 μg/ml. (In the present experiments the dosage of probenecid was probably supramaximal). From the data of Weiner et al. (10), at this plasma level the concentration of free probenecid would be about 60 μg/ml. Even granting the errors intrinsic in the calculation, the data suggest comparable degrees of inhibition of PAH transport at plasma levels of free or unbound drug of 14 μg/ml of iophenoxic acid and 60 μg/ml of probenecid, or, on a molar basis, 2 × 10^-5 and 2 × 10^-4 M, respectively.