NEW YORK (Reuters Health) - Codeine intoxication can occur in individuals who are ultra-rapid CYP2D6 metabolizers because of CYP2D6 gene duplication, Swiss investigators report in the December 30th issue of The New England Journal of Medicine.
Dr. Yvan Gasche from Geneva University Hospital and colleagues describe the case of a 62-year-old man who developed life-threatening opioid intoxication after ingesting “small doses” of codeine (25 mg three times a day) to relieve cough associated with pneumonia.
Codeine is metabolized by CYP2D6 into morphine, and genotyping showed that the patient had three or more functional CYP2D6 alleles, a finding consistent with ultra-rapid metabolism of codeine.
“The total amount of morphine and metabolites in our patient corresponded to 75 percent of the total amount of codeine present in his body,” Dr. Gasche and colleagues note. In contrast, the “usual amount of morphine that is produced after the administration of multiple doses of codeine rarely reaches 10 percent of the total amount of codeine in a person with extensive CYP2D6 metabolism.”
Furthermore, the patient was being treated with clarithromycin and voriconazole. These are known to inhibit CYP3A4, which aids in codeine clearance. The agents thus may have further reduced the clearance of codeine and increased the risk of an opioid overdose. In addition, the patient had reduced renal function.
Dr. Yoseph Caraco from Hadassah University Hospital in Jerusalem, Israel, author of an accompanying editorial, told Reuters Health that “with the use of genotyping or phenotyping for polymorphic enzymes like CYP2D6, CYP2C19 and CYP2C9, we can now account for some of the observed variability in response to drugs which are substrates of these specific enzymes.”
More importantly, he concluded, “such knowledge may be used prior to drug administration permitting drug and dose selection, which may fit the specific metabolic capacity of a given patient.”
N Engl J Med 2004;2827-2831,2867-2869.
MeSH Headings:Cytochrome P-450: Cytochromes: Drug Toxicity: Enzymes, Coenzymes, and Enzyme Inhibitors: Hydroxylases: Cytochrome P-450 CYP2D6: Chemicals and DrugsCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
