The Enhancement of Iopanoate Excretion by Taurocholate

Experiments in dogs equipped with Thomas cannulas show that the calculated maximum excretion rate (Emax) of iopanoic acid is closely linked to the rate of bile salt excretion (Gastroenterology 1978;74:174–181). The Emax increases in an apparently linear manner from 0.20–2.36 /μmole/min/kg as the rate of bile salt excretion increases from 0.21–2.62 μmole/min/kg. From the slope of the relation between the biliary excretion of bile salts and the Emax of iopanoate, it can be determined that 0.89 μmole of iopanoate is coupled with each μmole of bile salt. The mechanism by which bile salts enhance the Emax of iopanoate is difficult to determine from such studies. However, it is apparent that it is the taurocholate excretion per se and not the increase in bile flow that facilitates the excretion of iopanoate. Stimulation of bile flow with SC2644 (canalicular bile flow) or with secretin (ductular bile flow) has no influence on the rate of excretion of iopanoate. A physiochemical interaction between bile salts and iopanoate in bile could play a role in preventing back diffusion of iopanoate across the canalicular membrane. The coupling of iopanoate and bile salt molecules in bile at a ratio of 0.89 during maximum excretion of iopanoate is consistent with molecular ratios found between certain lipids and bile salts in mixed micelles. Because iopanoate is not a choleretic, it is possible that iopanoate is rendered osmotically inactive by entry into bile salt micelles. However, studies with other organic anions in rats indicate that binding to bile salt micelles does not always correlate with the facilitative action of bile salts on the biliary excretion of organic anions. Another possibility could be the mechanism postulated by Forker and Gibson for BSP. They propose that a carrier for BSP on the canalicular membrane reacts allosterically with taurocholate to produce, in effect, a second carrier with different kinetic parameters that can transport additional BSP. Goresky et al suggest that bile salts facilitate the biliary excretion of bilirubin by recruitment of the canalicular transport process in the centrilobular portion of the liver. The mechanism also could explain the influence of bile salts on iopanoate excretion. An important effect of bile salts on iopanoate excretion is suggested by the results of experiments in normal human volunteers. In these studies, 8 of 10 fasted volunteers failed to have gallbladder opacification with iopanoic acid compared to satis