Codeine Intoxication Associated with Ultrarapid CYP2D6 Metabolism

Divisions of Surgical and Medical Intensive Care, Geneva University Hospital, Switzerland.
New England Journal of Medicine (Impact Factor: 54.42). 01/2005; 351(27):2827-31. DOI: 10.1056/NEJMoa041888
Source: PubMed

ABSTRACT Life-threatening opioid intoxication developed in a patient after he was given small doses of codeine for the treatment of a cough associated with bilateral pneumonia. Codeine is bioactivated by CYP2D6 into morphine, which then undergoes further glucuronidation. CYP2D6 genotyping showed that the patient had three or more functional alleles, a finding consistent with ultrarapid metabolism of codeine. We attribute the toxicity to this genotype, in combination with inhibition of CYP3A4 activity by other medications and a transient reduction in renal function.

Download full-text


Available from: Jules Desmeules, Aug 21, 2015
  • Source
    • "Codeine is a commonly used medicine for symptoms such as pain and cough. Despite its uncertain therapeutic effect and the potential for life-threatening adverse reactions, codeine is easily available and affordable as a combination product or as a stand-alone opioid (Gasche et al., 2004; Chung, 2008). Codeine exhibits an affinity to micro-opioid receptors 200 times lower than morphine, with the capability of producing opiate intoxication, dependence, and withdrawal (Prommer , 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In past 2 decades, nonmedical consumption of cough mixture has become a serious social problem in certain regions of China. Cough mixture abuse causes psychiatric symptoms. Moreover, there has been an increasing concern about the physical disorders associated with cough mixture abuse. A retrospective chart review of hypokalemia related to cough mixture abuse between January 2009 and December 2012 was conducted in Guangzhou Brain Hospital, China. The charts were reviewed for 34 subjects with cough mixture abuse. Seven of 34 cough mixture abusers (20.6%) presented hypokalemia, with symptoms ranged from mild to severe limb weakness. Hypokalemia in these patients reduced after normalization of potassium. A high incidence of hypokalemia presents in cough mixture abusers. Cough mixture abuse might be one of the secondary causes of hypokalemia paralysis in young patients presenting to emergency departments.
    Journal of Addiction Medicine 04/2014; 8(3). DOI:10.1097/ADM.0000000000000033 · 1.71 Impact Factor
  • Source
    • "Severe respiratory depression is observed after morphine overdose or in the case of extremely high metabolizing rates of codeine to morphine [6] [7]. Amplification of the CYP2D6 gene was assumed to be the cause of some cases of death from respiratory depression after codeine administration [8] [9] [10] [11] [12] [13]. Therefore, genotyping of CYP2D6 prior to codeine administration has been recommended and a warning is issued in the official FDA drug label [14] [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We investigated whether morphine and its pro-drug codeine are substrates of the highly genetically polymorphic organic cation transporter OCT1 and whether OCT1 polymorphisms may affect morphine and codeine pharmacokinetics in humans. Morphine showed low transporter-independent membrane permeability (0.5×10(-6)cm/s). Morphine uptake was increased up to 4-fold in HEK293 cells overexpressing human OCT1. The increase was concentration-dependent and followed Michaelis-Menten kinetics (KM=3.4μM, VMAX=27pmol/min/mg protein). OCT1-mediated morphine uptake was abolished by common loss-of-function polymorphisms in the OCT1 gene and was strongly inhibited by drug-drug interactions with irinotecan, verapamil and ondansetron. Morphine uptake in primary human hepatocytes was strongly reduced by MPP(+), an inhibitor of organic cation transporters, and morphine was not a substrate of OCT3, the other organic cation transporter expressed in human hepatocytes. In concordance with the in vitro data, morphine plasma concentrations in healthy volunteers were significantly dependent on OCT1 polymorphisms. After codeine administration, the mean AUC of morphine was 56% higher in carriers of loss-of-function OCT1 polymorphisms compared to non-carriers (P=0.005). The difference remained significant after adjustment for CYP2D6 genotype (P=0.03). Codeine itself had high transporter-independent membrane permeability (8.2×10(-6)cm/s). Codeine uptake in HEK293 cells was not affected by OCT1 overexpression and OCT1 polymorphisms did not affect codeine AUCs. In conclusion, OCT1 plays an important role in the hepatocellular uptake of morphine. Carriers of loss-of-function OCT1 polymorphisms may be at higher risk of adverse effects after codeine administration, especially if they are also ultra-rapid CYP2D6 metabolizers.
    Biochemical pharmacology 07/2013; 86(5). DOI:10.1016/j.bcp.2013.06.019 · 4.65 Impact Factor
  • Source
    • "For instance, codeine is metabolized by CYP2D6 to morphine. In such cases, enhanced CYP2D6 activity (i.e., in CYP2D6 ultra-rapid metabolizers) predisposes one to opioid intoxication (Gasche et al. 2004). • CYP 2C19 (S-mephenytoin hydroxylase) acts on weakly or strongly basic drugs containing one hydrogen bond donor, or if there are functional groups containing carbon or sulfur double bonded to oxygen present in the substrate. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Space flight is one of the most extreme condi-tions encountered by humans. Advances in Omics meth-odologies (genomics, transcriptomics, proteomics, and metabolomics) have revealed that unique differences exist between individuals. These differences can be amplified in extreme conditions, such as space flight. A better under-standing of individual differences may allow us to develop personalized countermeasure packages that optimize the safety and performance of each astronaut. In this review, we explore the role of ''Omics'' in advancing our ability to: (1) more thoroughly describe the biological response of humans in space; (2) describe molecular attributes of individual astronauts that alter the risk profile prior to entering the space environment; (3) deploy Omics tech-niques in the development of personalized countermea-sures; and (4) develop a comprehensive Omics-based assessment and countermeasure platform that will guide human space flight in the future. In this review, we advance the concept of personalized medicine in human space flight, with the goal of enhancing astronaut safety and performance. Because the field is vast, we explore selected examples where biochemical individuality might signifi-cantly impact countermeasure development. These include gene and small molecule variants associated with: (1) metabolism of therapeutic drugs used in space; (2) one carbon metabolism and DNA stability; (3) iron metabo-lism, oxidative stress and damage, and DNA stability; and (4) essential input (Mg and Zn) effects on DNA repair. From these examples, we advance the case that widespread Omics profiling should serve as the foundation for aero-space medicine and research, explore methodological considerations to advance the field, and suggest why per-sonalized medicine may become the standard of care for humans in space.
    Metabolomics 06/2013; 9(6). DOI:10.1007/s11306-013-0556-3 · 3.97 Impact Factor
Show more