Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat.

Morphine was administered to rats by oral, intraportal, and intravenous routes in a dose of 7.6 mg . kg-1. From the serum concentration data after intraportal administration it was calculated that the first-pass elimination of morphine in the liver amounts to 72 +/- 2% (SD). The first-pass fraction eliminated after oral administration was 85 +/- 7% (SD), thus yielding a contribution by the gut mucosa of 46% to the overall first-pass elimination after an oral dose. The results were obtained with a general compartmental model which included the kinetics of enterohepatic recirculation. The oral availability was also estimated with the aid of pharmacological effect data. This availability was in good agreement with the corresponding value determined from the serum concentration data. The results suggest that morphine is subjected to enterohepatic recirculation and that the slowest phase of decline of morphine concentrations in serum might be due to this physiological process.