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Impact of cytochrome P450 variation on meperidine N-demethylation to the neurotoxic metabolite normeperidine.

Authors
  • Murray, Jessica L1
  • Mercer, Susan L1, 2
  • Jackson, Klarissa D1, 2
  • 1 Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy and Health Sciences, Nashville, TN, USA.
  • 2 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Type
Published Article
Journal
Xenobiotica; the fate of foreign compounds in biological systems
Publication Date
Feb 01, 2020
Volume
50
Issue
2
Pages
209–222
Identifiers
DOI: 10.1080/00498254.2019.1599465
PMID: 30902024
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

1. Meperidine is an opioid analgesic that undergoes N-demethylation to form the neurotoxic metabolite normeperidine. Previous studies indicate that meperidine N-demethylation is catalyzed by cytochrome P450 2B6 (CYP2B6), CYP3A4, and CYP2C19.2. The purpose of this study was to examine the relative P450 contributions to meperidine N-demethylation and to evaluate the effect of CYP2C19 polymorphism on normeperidine generation. Experiments were performed using recombinant P450 enzymes, selective chemical inhibitors, enzyme kinetic assays, and correlation analysis with individual CYP2C19-genotyped human liver microsomes.3. The catalytic efficiency (kcat/Km) for meperidine N-demethylation was similar between recombinant CYP2B6 and CYP2C19, but markedly lower by CYP3A4.4. In CYP2C19-genotyped human liver microsomes, normeperidine formation was significantly correlated with CYP2C19 activity (S-mephenytoin 4´-hydroxylation).5. CYP2C19 inhibitor (+)-N-3-benzylnirvanol and CYP3A inhibitor ketoconazole significantly reduced microsomal normeperidine generation by an individual donor with high CYP2C19 activity, whereas donors with lower CYP2C19 activity were sensitive to inhibition by ketoconazole but not benzylnirvanol.6. These findings demonstrate that the relative CYP3A4, CYP2B6, and CYP2C19 involvement in meperidine N-demethylation depends on the enzyme activities in individual human liver microsomal samples. CYP2C19 is likely an important contributor to normeperidine generation in individuals with high CYP2C19 activity, but additional factors influence inter-individual metabolite accumulation.

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