Precipitated withdrawal following codeine administration is dependent on CYP genotype

The role of metabolic polymorphism in the development of physical dependenc e to codeine was assessed in cytochrome P450 2D2 (CYP2D2) deficient Dark Ag outi and CYP2D2 intact Sprague-Dawley rats by assessment of the severity of naloxone precipitated withdrawal after codeine and morphine administration . Plasma morphine concentrations after codeine were significantly higher (P < 0.01) in Sprague-Dawley than in Dark Agouti rats with metabolic ratios o f 0.71 +/- 0.27 and 0.07 +/- 0.04, respectively. Withdrawal after codeine r esulted in significantly greater hypothermia (3.5-4 <degrees>C, P < 0.0001) in Sprague-Dawley animals compared to the other groups. Body weight loss w as similar for all groups ranging from 6.2 +/- 0.4 to 8.2 +/- 0.6 g. When s train and treatment data were combined, a relationship between body tempera ture and plasma morphine concentration could be described by the inverse Hi ll equation (r(2) = 0.76, EC50 = 556 +/- 121 ng/ml, n = 2.9 +/- 1.5). These data indicate that dependence and withdrawal after codeine administration are dependent on its bioconversion to morphine. (C) 2001 Elsevier Science B Y. All rights reserved.