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Am J Physiol Gastrointest Liver Physiol 274: G10-G20, 1998;
0193-1857/98 $5.00
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Vol. 274, Issue 1, G10-G20, January 1998

Hepatic uptake of hippurate: a multiple-indicator dilution, perfused rat liver study

Tsutomu Yoshimura1, Andreas J. Schwab2, Lei Tao1, Ford Barker1, and K. Sandy Pang1,3

1 Faculty of Pharmacy, University of Toronto, Toronto M5S 2S2; 3 Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1S1; and 2 McGill University Medical Clinic, Montreal General Hospital, and Department of Medicine, McGill University, Montreal, Québec, Canada H3G 1A4

The hepatic transport of hippuric acid (HA), a glycine-conjugated metabolite of benzoic acid that exhibits only modest plasma albumin binding (binding association constant of 2.1 × 103 M-1), was studied in the single-pass perfused rat liver (12 ml/min), using the multiple indicator dilution (MID) technique. The venous recovery of [3H]HA on portal venous injection of a MID dose containing a mixture of a set of noneliminated reference indicators and [3H]HA revealed a survival fraction of unity, corroborating the lack of disappearance of bulk HA from plasma. When the outflow recovery was fitted to the barrier-limited model of Goresky et al. (C. A. Goresky, G. G. Bach, and B. E. Nadeau. J. Clin. Invest. 52: 991-1009, 1973), the derived influx (PinS ) and efflux (PoutS ) permeability-surface area products were found to be dependent on the concentration of HA (1-930 µM); PinS and PoutS were ~3.5 times the plasma flow rate at low HA concentration, but decreased with increasing HA concentration. All values, however, greatly exceeded the expected contribution from passive diffusion, because the equilibrium distribution ratio of chloroform to buffer for HA was extremely low (0.0001 at pH 7.4). The tissue equilibrium partition coefficient (Pin/Pout, or ratio of influx to efflux rate constants, k1/k-1) was less than unity and decreased with concentration. The optimized apparent Michaelis-Menten constant and maximal velocity were 182 ± 60 µM and 12 ± 4 nmol · s-1 · g-1, respectively, for influx and 390 ± 190 µM and 29 ± 13 nmol · s-1 · g-1, respectively, for efflux. In the presence of L-lactate (20 mM), however, PinS for the uptake of HA (174 ± 3 µM) was reduced. Benzoic acid (10-873 µM) was also effective in reducing hepatic uptake of HA (5.3 ± 0.9 µM). These interactions suggest that MCT2, the monocarboxylate transporter that mediates the hepatic uptake of lactate and other monocarboxylic acids, may be involved in HA transport.

benzoic acid; L-lactate; influx and efflux coefficients; permeability-surface area product; carrier-mediated transport; monocarboxylic acid transporter; MCT2; plasma and tissue protein binding; rat liver perfusion


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