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.