Differences in excretion of hippurate, as a metabolite of benzoate and as an administered species, in the single-pass isolated perfused rat kidney explained

The extents of excretion of [C-14]hippurate and [H-3]hippurate were compare d in the single-pass, constant flow (8 ml/min) isolated rat kidney which wa s perfused simultaneously with tracer concentrations of [C-14]benzoate and [H-3]hippurate. The steady-state renal extraction ratio of [C-14]benzoate w as 0.26 +/- 0.04 and was associated with a renal clearance of 1.13 +/- 0.17 ml/min/g. The urinary clearance of [C-14]benzoic acid was low (0.011 +/- 0 .01 ml/min/g), yielding a low fractional excretion [unbound urinary clearan ce/glomerular filtration rate (GFR)] value of 0.27 +/- 0.19 and suggesting that glycination of [C-14]benzoate to [C-14]hippurate accounted almost comp letely for the total renal clearance. Fractional excretion for preformed [H -3]hippurate was eight times that of GFR, but the steady-state renal extrac tion ratio of preformed [H-3]hippurate, E{pmi} (0.24 +/- 0.05) was much low er than the apparent extraction ratio of the renally formed [C-14]hippuric acid [E{mi} = 0.39 +/- 0.09] (p < .05). The theoretical basis for the discr epancy was explored with mathematical formulations developed from a physiol ogically based model of the kidney. It was found that parent drug kinetic p arameters (transport and metabolic intrinsic clearance of benzoate) were un important for E{mi} or E{pmi}. Rather, the value of E-K{pmi} exceeded E-K{p mi} because of the ratio of efflux clearances at the basolateral and lumina l membranes for urate hippurate was less than 26.089, a value determined by the GFR, plasma renal flow, and the unbound fraction of hippurate of the s ystem that would render E{mi} to equal E{pmi} in the system. The influx cle arance for hippurate to enter from plasma to cell at the basolateral membra ne and the reabsorption clearance of hippurate to enter from tubular urine to cell at the luminal membrane failed to alter the ratio of E-K{mi}/E-K{pm i}.