A study of the inverse relationship between pKa and rate of renal excretion of phenylbutazone analogs in man and dog

Abstract

Renal clearance studies, in man and dog, were made of a series of phenylbutazone analogs, related in structure and similar in lipid solubility and binding to plasma protein (about 98 per cent in man) but differing widely in acidity (range of pKa, 2.0 to 5.5). It was found that the rate of renal excretion of these compounds varied inversely with their pKa. The more acidic analogs were rapidly excreted in man under the normal circumstances of acid urine (net secretion in clearance studies), the less acidic analogs were very slowly excreted (net reabsorption). Stop-flow studies in the dog revealed that peak secretion of the drugs, when demonstrable, occurred in the proximal tubular segment. Reabsorption occurred chiefly from the acidified urine of the more distal tubular segments, but the less acidic analogs may be appreciably reabsorbed more proximally also. Analysis of the data on the rate of excretion of the phenylbutazone analogs in acid and alkaline urine indicates that tubular reabsorption varies directly with the pKa of the compound and therefore is attributable to non-ionic back-diffusion. Tubular secretion of the phenylbutazone analogs, on the other hand, occurred under conditions necessitating the assumption of active tubular transport. While active tubular secretion could not be measured directly by the technics employed, particularly in the presence of concomitant tubular reabsorption, evidence is presented to suggest that the phenylbutazone analogs of lower pKa were secreted by the tubules more rapidly than were the compounds of higher pKa. It is therefore inferred that the inverse relationship between the acidity and the rate of renal excretion of the phenylbutazone analogs may represent the summation of what seem to be two distinct effects of the pKa: one directly relating pKa to non-ionic back-diffusion, the other, apparently, inversely relating pKa to the rate of active tubular secretion. It is further suggested that the effect of pKa on the rate of active tubular secretion may be associated also with the previously described inverse relationship of pKa to uricosuric potency of the phenylbutazone analogs. Whereas metabolically derived organic acids ordinarily are effectively conserved, by active processes of reabsorption or retention by the tubule cells, organic acids foreign to the body economy are gotten rid of by renal processes which vary in efficacy, depending in part upon the pKa of the compound. Acidic compounds of lower pKa are eliminated expeditiously, by vigorous active tubular secretion and such filtration as is permitted by the degree of binding to plasma proteins; there is no active tubular reabsorption; and, even if readily lipid-soluble, little non-ionic back-diffusion. Acidic compounds of higher pKa are eliminated at a slower rate. Active tubular secretion seems to be more sluggish; filtration is limited by the degree of plasma protein binding; and tubular reabsorption is more or less complete (if the compound is lipid-soluble) by non-ionic back-diffusion. Elimination of such drugs is facilitated by metabolic conversion to more readily excreted conjugates or degradation products. Acidic compounds of intermediate pKa are variably excreted as such and as metabolites in the urine. The relationship of these renal mechanisms to the “increased acidity” hypothesis of detoxication of organic acids by conjugation to form compounds of lower pKa, hence more rapidly excreted, is pointed out. Appreciation of such structure-excretion relationships may prove to be helpful in anticipating the rate of renal excretion and the plasma halflife of newly synthesized acidic and basic drugs.