CARRIER-MEDIATED ACTIVE-TRANSPORT OF THE GLUCURONIDE AND SULFATE OF OXY-5,7-DIMETHYL-2-METHYLAMINO-4-(3-PYRIDYLMETHYL) BENZOTHIAZOLE (E3040) INTO RAT-LIVER - QUANTITATIVE COMPARISON OF PERMEABILITY IN ISOLATEDHEPATOCYTES, PERFUSED LIVER AND LIVER IN-VIVO

The hepatic uptake of glucuronic acid and sulfate conjugates of oxy-5, 7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040), a dual inhibitor of 5-lipoxygenase and thromboxane A(2) synthetase, was investigated in rats. The biliary excretion clearance values for the g lucuronide and the sulfate, obtained after i.v. administration of E304 0, were similar and corresponded to approximately 30% of the hepatic b lood flow rate. The influx clearance values of E3040 conjugates in the presence of 3% bovine serum albumin, measured by a multiple indicator dilution method in the perfused liver, were 1.20 ml/min/g liver for t he glucuronide and 0.74 ml/min/g liver for the sulfate, which were twi ce and equal to the normal hepatic plasma flow rate, respectively, whi ch suggests the presence of an efficient transport system(s). The upta ke of E3040 conjugates into the isolated hepatocytes is mediated by Na +-independent active transport system(s), which is inhibited by dibrom osulfophthalein and bile acids. The uptake for the sulfate had high-af finity and high-capacity transport activity (K-m = 25 mu M; V-max = 7. 8 nmol/min/10(6) cells) compared with that for the glucuronide (K-m = 59 mu M; V-max = 2.2 nmol/min/10(6) cells). The uptakes of E3040 conju gates (glucuronide, sulfate) exhibited a mutual competitive inhibition . It is suggested that both conjugates share a multispecific organic a nion transporter located on the sinusoidal membrane.