In vitro identification of the cytochrome P450 isozymes involved in the N-demethylation of the active opioid metabolite nortilidine to bisnortilidine.

Naunyn-Schmiedeberg's Archives of Pharmacology
Isabel WustrowJ Weiss

Abstract

Tilidine exhibits the highest consumption of opioids in Germany. The prodrug is hepatically metabolised in a sequential N-demethylation reaction. Its primary metabolite nortilidine is a selective μ-opioid receptor agonist which can penetrate the blood-brain barrier. Cytochrome P450 isozymes (CYP) 3A4 and CYP2C19 were previously identified as isozymes mediating the formation of nortilidine. This study was set up to identify the enzymes and kinetics of the subsequent N-demethylation to bisnortilidine, thus being able to understand clinical interactions. Human liver microsomes and recombinant CYPs were used to investigate the metabolism of nortilidine to bisnortilidine. Nortilidine and bisnortilidine were quantified using liquid chromatography tandem mass spectrometry. Inhibitor screening kits were used to quantify the inhibition of CYP3A4, CYP2C19, CYP2B6 and CYP2D6 by bisnortilidine. Nortilidine metabolism to bisnortilidine followed the Michaelis-Menten kinetics with K (m) = 141.6 ± 15 μM and V (max) = 46.2 ± 3 nmol/mg/h. Inhibitors of CYP3A4, CYP2C19 and CYP2B6 inhibited this reaction. Assays with recombinant CYPs verified that the N-demethylation is catalysed by CYP3A4, CYP2C19 a...Continue Reading

References

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Citations

Jul 13, 2013·Substance Abuse : Official Publication of the Association for Medical Education and Research in Substance Abuse·Lukas RadbruchPeter Cremer-Schaeffer
Aug 11, 2015·The Journal of Pharmacy and Pharmacology·Dirk TheileJohanna Weiss
Sep 17, 2014·Basic & Clinical Pharmacology & Toxicology·Christine EichbaumGerd Mikus
Jan 29, 2013·European Journal of Pharmacology·Johanna WeissWalter Emil Haefeli
Nov 1, 2020·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Nayara Cristina Perez de AlbuquerqueAnderson Rodrigo Moraes de Oliveira

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