A new analysis method for disposition kinetics of enterohepatic circulation of diclofenac in rats.

The pharmacokinetics of diclofenac, which is definitely subject to enterohepatic circulation in rats, was evaluated. The pharmacokinetic model for enterohepatic circulation was constructed in the Laplace-transformed domain by means of the transfer function method of the signal flow. The transformed equations were simultaneously fitted to the time courses of plasma concentration averaged over two groups of rats [i.e. one with an intact enterohepatic circulation and the other without an enterohepatic circulation by means of the bile duct cannula (double-lines fitting)]. The transformed equations were also fitted to each plasma time course in the individual rat (single-line fitting). It was demonstrated that the estimated pharmacokinetic parameters by the single-line fitting almost coincided with those by the double-lines fitting. The local moments for a single pass through enterohepatic circulation were also calculated from the time courses of both the plasma concentration and the amount excreted into the bile. In the nonanesthetized group, the recirculation ratio (Fc) and the mean recirculation time (tc) of diclofenac were estimated to be 21.1% and 4.5 hr, respectively. The absorption ratio (Fa) and the mean absorption time (ta) from the intestinal tract were 52.2% and 4.29 hr, respectively. The experiments using bile duct cannulation revealed that the total amounts excreted into the bile were 14.4% in the anesthetized group and 40.4% in the nonanesthetized group of rats, and that diclofenac was excreted 95% as the glucuronide form and 5% as the intact form in both groups.