Metabolism of Morphine in the Perfused Rat Liver

Abstract Morphine concentrations in the recirculating plasma of a perfused rat liver preparation declined in a monoexponential manner with a half–life of 5.3 ± 0.4 min. The mean hepatic clearance was calculated to 13.1 ± 1.0 ml–min.^–1, and using an average blood flow of 17.3 ml min.^–1 this corresponds to an extraction ratio of 0.76 ± 0.02. In experiments with steady state concentration of morphine almost identical results were obtained. Measurements of different morphine concentrations in the in– and outflow of plasma of the liver yielded a mean clearance of 13.3 ± 0.7 ml–min.^–1 and a mean extraction ratio of 0.77 ± 0.03, indicating a constant clearance at different concentrations. The clearance of morphine in the perfused liver experiments was in close agreement with an in vivo calculated hepatic clearance of 75 % of the total body clearance. It is concluded that the blood flow to the liver can be an important factor in determining availability of orally administered morphine, and that the high hepatic extraction of this drug can explain the low effectiveness of this mode of administration.