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                            Library & Multimedia
 In vitro inhibition of methadone and oxycodone cytochrome P450-dependent metabolism: Reversible inhibition by H2-receptor agonists and proton pump inhibitors
NCJ Number
              255735
Journal

*Journal of Analytical Toxicology* Volume: 37 Dated: 2013 Pages: 476-485
Author(s)
          David E. Moody;
                        Fenyun Liu;
                        Wenfang B. Fang
Date Published

2013
Length
              10 pages
Annotation
              This article examinesthe forensic science aspects of deaths (intentional or accidental, self-inflicted, a result of a medical misadventure, or some other reason) associated with opioid use, and the relationship of increased use of opioids in pain management and abuse of prescribed medications.
Abstract
              *In vitro*inhibition of oxycodone metabolism to noroxycodone and oxymorphone and*R*- and*S*-methadone metabolism to*R*- and*S*-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) was measured for four H2-receptor antagonists and five proton-pump inhibitors (PPIs) using human liver microsomes (HLM) and cDNA-expressed human cytochrome P450s (rCYPs). Inhibitors were first incubated with HLM at three concentrations with and without preincubation of inhibitor, enzyme source and reducing equivalents to also screen for time-dependent inhibition (TDI). Cimetidine and famotidine (10–1,000 μM) inhibited all the four pathways >50%. Nizatidine and ranitidine did not. All the five PPIs (1–200 μM) inhibited one or more pathways >50%. Half maximal inhibitory concentrations (IC50s) were then determined using rCYPs. Cimetidine and famotidine both inhibited CYP3A4-mediated formation of noroxycodone and CYP2D6-mediated formation of oxymorphone, and famotidine inhibited CYP3A4-mediated formation of*R*- and*S*-EDDP, but IC50s were so high that only >10× therapeutic concentrations may have potential for reversible*in vivo*inhibition. The PPIs were more potent inhibitors; many have the potential for reversible*in vivo*inhibition at therapeutic concentrations. Omeprazole, esomeprazole and pantoprazole had greater effects on CYP3A4-mediated reactions, whereas lansoprazole was selective for CYP2D6-mediated formation of oxymorphone. Preincubation enhanced cimetidine inhibition of noroxycodone formation and rabeprazole inhibition of all pathways. Future studies will explore irreversible TDI. (Published Abstract Provided)
      
  
          Additional Details
Grant Number(s)
        2011-DN-BX-K532


  
  
        
  Agencies
        NIJ-Sponsored


  
  
        
  Publication Type
        Research (Applied/Empirical)


  
  
        
  Award
        Prediction of drug interactions with methadone, buprenorphine and oxycodone from in vitro inhibition of metabolism
    
  
  
Date Published: January 1, 2013
    
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