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Precipitated withdrawal following codeine administration is dependent on CYP genotype
M Chew1, J M White, A A Somogyi
1Department of Clinical and Experimental Pharmacology, Adelaide University, 5005, Adelaide, Australia.
European Journal of Pharmacology
|August 22, 2001
Summary
Metabolic polymorphism influences codeine dependence. Codeine bioconversion to morphine is critical for physical dependence and withdrawal symptoms, like hypothermia, in rats.
Area of Science:
- Pharmacology
- Toxicology
- Genetics
Background:
- Metabolic polymorphism, particularly in cytochrome P450 enzymes, can significantly alter drug efficacy and toxicity.
- Understanding these metabolic pathways is crucial for predicting drug response and dependence liability.
Purpose of the Study:
- To investigate the role of metabolic polymorphism in the development of physical dependence on codeine.
- To compare codeine and morphine withdrawal severity in rats with differing cytochrome P450 2D2 (CYP2D2) activity.
Main Methods:
- Utilized Dark Agouti (CYP2D2 deficient) and Sprague-Dawley (CYP2D2 intact) rats.
- Assessed naloxone-precipitated withdrawal severity after codeine and morphine administration.
- Measured plasma morphine concentrations and monitored hypothermia and body weight loss.
Main Results:
- Sprague-Dawley rats exhibited significantly higher plasma morphine concentrations after codeine administration compared to Dark Agouti rats.
- Codeine withdrawal induced significantly greater hypothermia in Sprague-Dawley rats.
- A clear relationship was established between plasma morphine concentration and body temperature during withdrawal.
Conclusions:
- Codeine dependence and withdrawal are critically dependent on its metabolic conversion to morphine.
- CYP2D2 activity plays a significant role in modulating the pharmacological effects and dependence potential of codeine.