CYP2D6 Phenotype-Specific Codeine Population Pharmacokinetics. (1st March 2015)

• Record Type: Journal Article
• Authors: Linares, Oscar A.; Fudin, Jeffrey; Schiesser, William E.; Daly Linares, Annemarie L.; Boston, Raymond C.
• Is Part Of: Journal of pain & palliative care pharmacotherapy. Volume 29:Number 1(2015)
• Page Start: 4
• Page End: 15
• Publication Date: 2015-03-01
• Subjects: codeine -- CYP2D6 -- CYP3A4 -- CYP2C8 -- morphine -- pharmacogenetics -- pharmacogenomics -- clinical pharmacokinetics -- clinical pharmacology -- population pharmacokinetics; Pain -- Treatment -- Periodicals; Analgesia -- Periodicals; Palliative treatment -- Periodicals; Analgesics -- Therapeutic use -- Periodicals; Pain -- drug therapy -- Periodicals; Pain -- prevention & control -- Periodicals; Palliative Care -- Periodicals; Analgesics -- therapeutic use -- Periodicals; 616.994
• DOI: 10.3109/15360288.2014.997854
• Languages: English
• ISSNs: 1536-0288

Abstract

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.