Pharmacokinetic analysis of enterohepatic circulation of 4-[2-(4-isopropylbenzamido)ethoxy]benzoic acid. Effect of intramolecular rearrangement of its acyl glucuronide.

The enterohepatic circulation of 4-[2-(4-isopropylbenzamido)ethoxy]benzoic acid (PBAB) was studied in rats after an iv administration of 30 mg/kg. After the bolus injection, the PBAB concentrations in the plasma decreased rapidly, then increased to a peak concentration at 4 hr. Over a 6-hr period, 52% of the dose (Fe) was excreted in the bile as 1 beta-O-acyl glucuronide of PBAB (1 beta-PG). Elimination of PBAB from the plasma of bile duct-cannulated rats was more rapid than for the sham-operated rats. These results suggest that PBAB undergoes enterohepatic circulation. The equation for an enterohepatic circulation model was fitted to the plasma PBAB concentrations for intact rats using the program MULTI (FILT) to estimate the single circulating fraction (Fc) (bile----intestine----systemic circulation). The Fc value was 0.072, which means that 7.2% of the dose was reabsorbed to systemic circulation during the first cycle. The fraction (Fa) reabsorbed from small intestine to systemic circulation during first cycle can be estimated by the formula Fa = Fo/Fa. The Fa value obtained was 14% of the dose, which was smaller than the Fa' (26% of the dose) standing for systemic availability of PBAB after oral dosing. When 1 beta-PG was incubated with bile for 2 hr, 79% was transformed to beta-glucuronidase-resistant isomers by intramolecular acyl migration. We consider that the acyl migration of 1 beta-PG in the small intestine or bile causes the difference between Fa and Fa' values, and decreases the enterohepatic circulation of PBAB.