May 2014

J Anal Toxicol. 2013 Oct;37(8):476-85

In vitro inhibition of methadone and oxycodone cytochrome P450-dependent metabolism: reversible inhibition by H2-receptor agonists and proton-pump inhibitors

Moody DE, Liu F, Fang WB

The effect of Histamine 2 (H2)-receptor antagonists and proton-pump inhibitors (PPIs) on the metabolism of oxycodone and methadone was evaluated in an in vitro study using human liver microsomes expressing cytochrome P450s. Inhibition of oxycodone metabolism to noroxycodone and oxymorphone and methadone metabolism to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) was measured for four H2-receptor antagonists and five PPIs. The H2-receptor antagonists cimetidine and famotidine inhibited the metabolism of oxycodone and methadone, but this was weak reversible inhibition occurring only at concentrations over 10 times those found therapeutically. Nizatidine and ranitidine did not influence oxycodone or methadone metabolism. The PPIs tested were more potent inhibitors and many have the potential for reversible in vivo inhibition at therapeutic concentrations with all the PPIs inhibiting one or more of the metabolic pathways by over 50%. Omeprazole, esomeprazole and pantoprazole had greater effects on CYP3A4-mediated reactions, whereas lansoprazole was selective for CYP2D6-mediated formation of oxymorphone. Further studies are needed to evaluate the clinical implications of these in vitro findings.

Jason Boland