Carrier-mediated active transport of the glucuronide and sulfate of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) into rat liver: quantitative comparison of permeability in isolated hepatocytes, perfused liver and liver in vivo

The hepatic uptake of glucuronic acid and sulfate conjugates of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040), a dual inhibitor of 5-lipoxygenase and thromboxane A2 synthetase, was investigated in rats. The biliary excretion clearance values for the glucuronide and the sulfate, obtained after i.v. administration of E3040, were similar and corresponded to approximately 30% of the hepatic blood 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 the glucuronide and 0.74 ml/min/g liver for the sulfate, which were twice and equal to the normal hepatic plasma flow rate, respectively, which suggests the presence of an efficient transport system(s). The uptake of E3040 conjugates into the isolated hepatocytes is mediated by Na(+)-independent active transport system(s), which is inhibited by dibromosulfophthalein and bile acids. The uptake for the sulfate had high-affinity and high-capacity transport activity (Km = 25 microM; Vmax = 7.8 nmol/min/10(6) cells) compared with that for the glucuronide (Km = 59 microM; Vmax = 2.2 nmol/min/10(6) cells). The uptakes of E3040 conjugates (glucuronide, sulfate) exhibited a mutual competitive inhibition. It is suggested that both conjugates share a multispecific organic anion transporter located on the sinusoidal membrane.