Isolation, Hepatic Distribution, and Intestinal Absorption of the Glucuronide Metabolite of Iopanoic Acid

Abstract

Iopanoic acid (Telepaque) is an oral contrast agent that is absorbed from the intestinal tract, removed from the blood by the liver, conjugated with glucuronide acid in the liver, transported across the canalicular membrane into the biliary tree, and, ultimately, collected and concentrated in the gallbladder. The authors performed a variety of experiments to assess the role of the conjugation step on the excretion of iopanoic acid (IOP). A procedure was developed to isolate and purify the glucuronide metabolite of iopanoic acid (IOP-G) from dog bile. IOP-G from bile was bound to a column of neutral resin (Amberlite XAD-2) and washed with several solutions to remove some of the biliary contaminants selectively. IOP-G was eluted from the column, isolated and purified by ether extraction, and recrystallized with heptane. Final yield of IOP-G varied from 60–75% with a purity of approximately 95%. The maximum rate of biliary excretion of iopanoate (Emax) in rats was achieved with a dose of 300 μmol/kg of either IOP or IOP-G. The Emax after giving IOP-G was 60% higher than the Emax after administering IOP. Neither IOP nor IOP-G were choleretic. Therefore, the biliary concentration of iopanoate was higher after administering IOP-G than when IOP was given. Additional studies were performed to determine the effect of bile salt excretion on the Emax of iopanoate in rats following the intravenous infusion of either IOP or IOP-G. Taurocholate was given intravenously at 2 and 4 μmol/min/kg. Bile salt excretion enhanced the Emax of iopanoate in rats in a similar manner as that previously found in dogs. The effect of taurocholate on the Emax when IOP-G compared to IOP was given was determined. The hepatic concentration of iopanoate was significantly higher after IOP-G than after IOP administration. In addition, the liver concentration was four times greater than the plasma concentration. The distribution of iopanoate among the various subcellular fractions after IOP and IOP-G injection was determined. It is possible that the difference between the plasma and hepatic concentration of IOP-G is sufficient to opacify the liver on CT scan. Following elimination from the gallbladder, conjugates of contrast agents are believed to be poorly absorbed from the intestine. However, we found significant absorption of IOP-G from isolated jejunal loops in dogs. This is in agreement with recent reports indicating that there is considerable enterohepatic circulation of IOP-G. The rate of absorption (intestinal flux, Jd) was determined from the maximum aqueous solubility (Cm) and the permeability coefficient (P) in the intestine (Jd = Cm ± P). Although the permeability of IOP-G is approximately one-third that of IOP, the intestinal flux is 10 times greater because IOP-G is 40 times more soluble in aqueous solution than IOP. These data suggest that an enterohepatic circulation of IOP-G occurs and may account for persistent or recurring gallbladder visualization.