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 [14C]hippurate and [3H]hippurate were compared in the single-pass, constant flow (8 ml/min) isolated rat kidney which was perfused simultaneously with tracer concentrations of [14C]benzoate and [3H]hippurate. The steady-state renal extraction ratio of [14C]benzoate was 0.26 +/- 0.04 and was associated with a renal clearance of 1.13 +/- 0.17 ml/min/g. The urinary clearance of [14C]benzoic acid was low (0.011 +/- 0.01 ml/min/g), yielding a low fractional excretion [unbound urinary clearance/glomerular filtration rate (GFR)] value of 0.27 +/- 0.19 and suggesting that glycination of [14C]benzoate to [14C]hippurate accounted almost completely for the total renal clearance. Fractional excretion for preformed [3H]hippurate was eight times that of GFR, but the steady-state renal extraction ratio of preformed [3H]hippurate, E(pmi) (0.24 +/- 0.05) was much lower than the apparent extraction ratio of the renally formed [14C]hippuric acid [E(mi) = 0.39 +/- 0.09] (p <.05). The theoretical basis for the discrepancy was explored with mathematical formulations developed from a physiologically based model of the kidney. It was found that parent drug kinetic parameters (transport and metabolic intrinsic clearance of benzoate) were unimportant for E(mi) or E(pmi). Rather, the value of EK(mi) exceeded EK(pmi) because of the ratio of efflux clearances at the basolateral and luminal membranes for hippurate [corrected] was less than 26.089, a value determined by the GFR, plasma renal flow, and the unbound fraction of hippurate of the system that would render E(mi) to equal E(pmi) in the system. The influx clearance for hippurate to enter from plasma to cell at the basolateral membrane and the reabsorption clearance of hippurate to enter from tubular urine to cell at the luminal membrane failed to alter the ratio of EK(pmi)/EK(mi).