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
• 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

Annotation

This article examines the 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)