Metabolism of 14C-codeine in the isolated, perfused rat liver

The metabolism of 14C-codeine in the isolated rat liver was studied in single-pass and recirculation perfusion experiments. The perfusate, a semi-synthetic medium with bovine erythrocytes, was delivered at a constant rate (12 ml/min.) and contained codeine in the range of 3-57 nmol/ml. Samples of perfusate were collected and analyzed for codeine and its metabolites after extraction and thin-layer chromatographic separation. In single-pass perfusion, steady state was reached within 20 min. The codeine concentration in the effluent perfusate varied from 17 to 48% of that in the affluent corresponding to extraction ratios of 0.83 to 0.52. There was a significant negative correlation between codeine dose and extraction ratio (r = 0.86, P less than 0.05, N = 6). The steady state concentration of free and conjugated morphine made a total of 21 to 49% of the molar concentration of codeine at the inflow side. The recovery of radioactivity at the end of the perfusions was on an average 89%. In recirculation perfusion experiments the codeine extraction ratios varied from 0.65 to 0.35. The amount of free morphine in the reservoir increased to a maximum within 25-45 min. Our results suggest a relatively high hepatic first-pass metabolism of codeine in the rat which is apparently dose-dependent. The quantitatively most significant metabolites of codeine are morphine and conjugated morphine. The rate and extent of morphine formation is compatible with the hypothesis that metabolically produced morphine may be responsible for the analgesic effect of codeine.