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Am J Physiol Gastrointest Liver Physiol 280: G1124-G1136, 2001;
0193-1857/01 $5.00
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Vol. 280, Issue 6, G1124-G1136, June 2001

Hepatic uptake and metabolism of benzoate: a multiple indicator dilution, perfused rat liver study

Andreas J. Schwab1,2, Lei Tao3, Tsutomu Yoshimura3, André Simard1, Ford Barker3, and K. Sandy Pang3,4

1 McGill University Medical Clinic, Montreal General Hospital and 2 Department of Medicine, McGill University, Montreal, Quebec H3G 1A4; 3 Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 2S2; and 4 Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8

Multiple, noneliminated references (51Cr-labeled erythrocytes, 125I-albumin, [14C]- or [3H]sucrose, and [2H]2O), together with [3H]hippurate or [14C]benzoate, were injected simultaneously into the portal vein of the perfused rat liver during single-pass delivery of benzoate (5-1,000 µM) and hippurate (5 µM) to investigate hippurate formation kinetics and transport. The outflow dilution data best fit a space-distributed model comprising vascular and cellular pools for benzoate and hippurate; there was further need to segregate the cellular pool of benzoate into shallow (cytosolic) and deep (mitochondrial) pools. Fitted values of the membrane permeability-surface area products for sinusoidal entry of unbound benzoate were fast and concentration independent (0.89 ± 0.17 ml · s-1 · g-1) and greatly exceeded the plasma flow rate (0.0169 ± 0.0018 ml · s-1 · g-1), whereas both the influx of benzoate into the deep pool and the formation of hippurate occurring therein appeared to be saturable. Results of the fit to the dilution data suggest rapid uptake of benzoate, with glycination occurring within the deep and not the shallow pool as the rate-determining step.

membrane permeability; mathematical models; mitochondria; glycine conjugation


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