The CYP2D6 gene determines oxycodone's phenotype-specific addictive potential: implications for addiction prevention and treatment.
We propose a hypothesis for predicting addictive potential of oral drugs, in general, and oxycodone's addictive potential, in particular. We hypothesize that a patient's CYP2D6 phenotype determines oxycodone's addictive potential, in part, via genotype-specific regulation of its clearance; although, other possible modulators of oxycodone's addiction potential exist. For example, brain CYPs related to phenotype could be involved. To pilot test our hypothesis, we used a mathematical model which postulates that oxycodone's addictive potential is given by: LAP=E/(ka/ke), where LAP represents addictive potential, E represents euphoric potency, ka is the absorption rate constant of drug from the gastrointestinal tract, and ke is the systemic elimination rate constant of drug by all processes responsible for its removal from plasma. Using CYP2D6 phenotype-specific oxycodone pharmacokinetic parameter values derived from published data, our hypothesis predicted that the canonical order of oxycodone's addictive potential was UM>EM>IM>PM, with corresponding LAP values of 0.24, 0.21, 0.17, and 0.15 respectively. Our hypothesis about oxycodone's addictive potential may provide a unifying approach useful for both personalized medicine dosing and predicting addictive potential of oral drugs in humans, since it is based on both oxycodone's pharmacogenetics and pharmacokinetics.
Plymouth Pharmacokinetic Modeling Study Group, 46425 Southview Lane, Plymouth, MI 48170, USA. Electronic address: OALinaresMD@gmail.com.
Oscar A
OA
Linares
Plymouth Pharmacokinetic Modeling Study Group, 46425 Southview Lane, Plymouth, MI 48170, USA.
David
D
Daly
Cedars-Sinai Medical Center, Biomedical Sciences Division, 8700 Beverly Boulevard, West Hollywood, CA 90048, USA.
Darko
D
Stefanovski
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, 3600 Market Street, Philadelphia, PA 19104-2646, USA.
Raymond C
RC
Boston
D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009293:Opioid-Related Disorders / Q000235:genetics / Q000517:prevention & control*; D010098:Oxycodone / Q000009:adverse effects*; D010641:Phenotype
D010098:Oxycodone; D019389:Cytochrome P-450 CYP2D6