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The CYP2D6 gene determines oxycodone's phenotype-specific addictive potential: implications for addiction prevention and treatment.

Authors
  • Linares, Oscar A1
  • Daly, David2
  • Stefanovski, Darko3
  • Boston, Raymond C4
  • 1 Plymouth Pharmacokinetic Modeling Study Group, 46425 Southview Lane, Plymouth, MI 48170, USA. Electronic address: [email protected]
  • 2 Plymouth Pharmacokinetic Modeling Study Group, 46425 Southview Lane, Plymouth, MI 48170, USA.
  • 3 Cedars-Sinai Medical Center, Biomedical Sciences Division, 8700 Beverly Boulevard, West Hollywood, CA 90048, USA.
  • 4 Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, 3600 Market Street, Philadelphia, PA 19104-2646, USA.
Type
Published Article
Journal
Medical hypotheses
Publication Date
Mar 01, 2014
Volume
82
Issue
3
Pages
390–394
Identifiers
DOI: 10.1016/j.mehy.2014.01.010
PMID: 24495562
Source
Medline
License
Unknown

Abstract

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.

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