CODEINE O-DEMETHYLATION - RAT STRAIN DIFFERENCES AND THE EFFECTS OF INHIBITORS

The oxidative metabolism of more than 20 drugs (e.g. sparteine, debrisoquine, dextromethorphan) is mediated by cytochrome P450IID6. Codeine O-demethylation to morphine was recently demonstrated to co-segregate with the polymorphic metabolism of debrisoquine and dextromethorphan. The female Dark-Agouti rat (DA) is an animal model for the poor metabolizer phenotype (PM) using debrisoquine or dextromethorphan as substrates. Studies was carried out to evaluate codeine metabolism in liver microsomes from female DA and Sprague-Dawley (SD) rats. The intrinsic clearance of codeine to morphine was 10-fold lower in DA rats due to a 5-fold higher K(m) (287 vs 49-mu-M) and a 2-fold lower V(max) (48 vs 94 nmol/mg/hr). Nineteen drugs were tested for inhibition of codeine O-demethylation. The four most potent competitive inhibitors were dextromethorphan (K(i) = 2.53-mu-M), propafenone (K(i) = 0.58-mu-M), racemic methadone (K(i) = 0.3-mu-M) and quinine (K(i) = 0.07-mu-M). The differences in morphine formation from codeine between SD and DA rats and the inhibition results show that this animal model appears to be a suitable model for the human EM and PM phenotypes, respectively. These strains could be used to study the pharmacodynamic consequences of the genetic polymorphism in codeine O-demethylation, and the effects of metabolic inhibitors. The outcome of these studies could impact on the therapy of pain control.