title: Precipitated withdrawal following codeine administration is dependent on CYP genotype.
abstract: The role of metabolic polymorphism in the development of physical dependence to codeine was assessed in cytochrome P450 2D2 (CYP2D2) deficient Dark Agouti 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 of 0.71 +/- 0.27 and 0.07 +/- 0.04, respectively. Withdrawal after codeine resulted in significantly greater hypothermia (3.5-4 degrees C, P<0.0001) in Sprague-Dawley animals compared to the other groups. Body weight loss was similar for all groups ranging from 6.2 +/- 0.4 to 8.2 +/- 0.6 g. When strain and treatment data were combined, a relationship between body temperature and plasma morphine concentration could be described by the inverse Hill equation (r(2)=0.76, EC(50)=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.
authors.affiliation: Department of Clinical and Experimental Pharmacology, Adelaide University, 5005, Adelaide, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Chew
authors.forename: J M
authors.initials: JM
authors.lastname: White
authors.forename: A A
authors.initials: AA
authors.lastname: Somogyi
authors.forename: F
authors.initials: F
authors.lastname: Bochner
authors.forename: R J
authors.initials: RJ
authors.lastname: Irvine
mesh_terms: D000701:Analgesics, Opioid / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001831:Body Temperature; D001835:Body Weight; D003061:Codeine / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics*; D005260:Female; D005838:Genotype; D009020:Morphine / Q000097:blood / Q000494:pharmacology; D009270:Naloxone / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome
chemical_list: D000701:Analgesics, Opioid; D009270:Naloxone; D009020:Morphine; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C119985:Cyp2d2 protein, rat; D003061:Codeine