title: CYP2D6 phenotype-specific codeine population pharmacokinetics.
abstract: Codeine's metabolic fate in the body is complex, and detailed quantitative knowledge of it, and that of its metabolites is lacking among prescribers. We aimed to develop a codeine pharmacokinetic pathway model for codeine and its metabolites that incorporates the effects of genetic polymorphisms. We studied the phenotype-specific time courses of plasma codeine, codeine-6-glucoronide, morphine, morphine-3-glucoronide, and morphine-6-glucoronide. A codeine pharmacokinetic pathway model accurately fit the time courses of plasma codeine and its metabolites. We used this model to build a population pharmacokinetic codeine pathway model. The population model indicated that about 10% of a codeine dose was converted to morphine in poor-metabolizer phenotype subjects. The model also showed that about 40% of a codeine dose was converted to morphine in EM subjects, and about 51% was converted to morphine in ultrarapid-metabolizers. The population model further indicated that only about 4% of MO formed from codeine was converted to morphine-6-glucoronide in poor-metabolizer phenotype subjects. The model also showed that about 39% of the MO formed from codeine was converted to morphine-6-glucoronide in extensive-metabolizer phenotypes, and about 58% was converted in ultrarapid-metabolizers. We conclude, a population pharmacokinetic codeine pathway model can be useful because beyond helping to achieve a quantitative understanding the codeine and MO pathways, the model can be used for simulation to answer questions about codeine's pharmacogenetic-based disposition in the body. Our study suggests that pharmacogenetics for personalized dosing might be most effectively advanced by studying the interplay between pharmacogenetics, population pharmacokinetics, and clinical pharmacokinetics.
authors.forename: Oscar A
authors.initials: OA
authors.lastname: Linares
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Fudin
authors.forename: William E
authors.initials: WE
authors.lastname: Schiesser
authors.forename: Annemarie L
authors.initials: AL
authors.lastname: Daly Linares
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Boston
mesh_terms: D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D003061:Codeine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D006801:Humans; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000097:blood; D009022:Morphine Derivatives / Q000097:blood; D010597:Pharmacogenetics; D010641:Phenotype; D011110:Polymorphism, Genetic
chemical_list: D000701:Analgesics, Opioid; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D009020:Morphine; C061773:codeine-6-glucuronide; D019389:Cytochrome P-450 CYP2D6; C018108:morphine-3-glucuronide; D003061:Codeine
keywords: CYP2C8; CYP2D6; CYP3A4; clinical pharmacokinetics; clinical pharmacology; codeine; morphine; pharmacogenetics; pharmacogenomics; population pharmacokinetics