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CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes.

Abstract

Meperidine is an opioid analgesic metabolized in the liver by N-demethylation to normeperidine, a potent stimulant of the central nervous system. The purpose of this study was to identify the human cytochrome P450 (P450) enzymes involved in normeperidine formation. Our in vitro studies included 1) screening 16 expressed P450s for normeperidine formation, 2) kinetic experiments on human liver microsomes and candidate P450s, and 3) correlation and inhibition experiments using human hepatic microsomes. After normalization by its relative abundance in human liver microsomes, CYP2B6, CYP3A4, and CYP2C19 accounted for 57, 28, and 15% of the total intrinsic clearance of meperidine. CYP3A5 and CYP2D6 contributed to < 1%. Formation of normeperidine significantly correlated with CYP2B6-selective S-mephenytoin N-demethylation (r = 0.88, p < 0.0001 at 75 > microM meperidine, and r = 0.89, p < 0.0001 at 350 microM meperidine, n = 21) and CYP3A4-selective midazolam 1'-hydroxylation (r = 0.59, p < 0.01 at 75 microM meperidine, and r = 0.55, p < 0.01 at 350 microM meperidine, n = 23). No significant correlation was observed with CYP2C19-selective S-mephenytoin 4'-hydroxylation (r = 0.36, p = 0.2 at 75 microM meperidine, and r = 0.02, p = 0.9 at 350 microM meperidine, n = 13). An anti-CYP2B6 antibody inhibited normeperidine formation by 46%. In contrast, antibodies inhibitory to CYP3A4 and CYP2C8/9/18/19 had little effect (<14% inhibition). Experiments with thiotepa and ketoconazole suggested inhibition of microsomal CYP2B6 and CYP3A4 activity, whereas studies with fluvoxamine (a substrate of CYP2C19) were inconclusive due to lack of specificity. We conclude that normeperidine formation in human liver microsomes is mainly catalyzed by CYP2B6 and CYP3A4, with a minor contribution from CYP2C19.

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  • Authors+Show Affiliations

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    University of Chicago, Department of Medicine, Section of Hematology-Oncology, 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637, USA.

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    MeSH

    Aryl Hydrocarbon Hydroxylases
    Cytochrome P-450 CYP2B6
    Cytochrome P-450 CYP2C19
    Cytochrome P-450 CYP3A
    Cytochrome P-450 Enzyme System
    Fluvoxamine
    Humans
    Hydroxylation
    Isoenzymes
    Ketoconazole
    Meperidine
    Mephenytoin
    Microsomes, Liver
    Mixed Function Oxygenases
    Oxidoreductases, N-Demethylating
    Recombinant Proteins
    Thiotepa

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't
    Research Support, U.S. Gov't, P.H.S.

    Language

    eng

    PubMed ID

    15319333

    Citation

    Ramírez, Jacqueline, et al. "CYP2B6, CYP3A4, and CYP2C19 Are Responsible for the in Vitro N-demethylation of Meperidine in Human Liver Microsomes." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 32, no. 9, 2004, pp. 930-6.
    Ramírez J, Innocenti F, Schuetz EG, et al. CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes. Drug Metab Dispos. 2004;32(9):930-6.
    Ramírez, J., Innocenti, F., Schuetz, E. G., Flockhart, D. A., Relling, M. V., Santucci, R., & Ratain, M. J. (2004). CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 32(9), pp. 930-6.
    Ramírez J, et al. CYP2B6, CYP3A4, and CYP2C19 Are Responsible for the in Vitro N-demethylation of Meperidine in Human Liver Microsomes. Drug Metab Dispos. 2004;32(9):930-6. PubMed PMID: 15319333.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes. AU - Ramírez,Jacqueline, AU - Innocenti,Federico, AU - Schuetz,Erin G, AU - Flockhart,David A, AU - Relling,Mary V, AU - Santucci,Raymond, AU - Ratain,Mark J, PY - 2004/8/21/pubmed PY - 2005/6/24/medline PY - 2004/8/21/entrez SP - 930 EP - 6 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab. Dispos. VL - 32 IS - 9 N2 - Meperidine is an opioid analgesic metabolized in the liver by N-demethylation to normeperidine, a potent stimulant of the central nervous system. The purpose of this study was to identify the human cytochrome P450 (P450) enzymes involved in normeperidine formation. Our in vitro studies included 1) screening 16 expressed P450s for normeperidine formation, 2) kinetic experiments on human liver microsomes and candidate P450s, and 3) correlation and inhibition experiments using human hepatic microsomes. After normalization by its relative abundance in human liver microsomes, CYP2B6, CYP3A4, and CYP2C19 accounted for 57, 28, and 15% of the total intrinsic clearance of meperidine. CYP3A5 and CYP2D6 contributed to < 1%. Formation of normeperidine significantly correlated with CYP2B6-selective S-mephenytoin N-demethylation (r = 0.88, p < 0.0001 at 75 > microM meperidine, and r = 0.89, p < 0.0001 at 350 microM meperidine, n = 21) and CYP3A4-selective midazolam 1'-hydroxylation (r = 0.59, p < 0.01 at 75 microM meperidine, and r = 0.55, p < 0.01 at 350 microM meperidine, n = 23). No significant correlation was observed with CYP2C19-selective S-mephenytoin 4'-hydroxylation (r = 0.36, p = 0.2 at 75 microM meperidine, and r = 0.02, p = 0.9 at 350 microM meperidine, n = 13). An anti-CYP2B6 antibody inhibited normeperidine formation by 46%. In contrast, antibodies inhibitory to CYP3A4 and CYP2C8/9/18/19 had little effect (<14% inhibition). Experiments with thiotepa and ketoconazole suggested inhibition of microsomal CYP2B6 and CYP3A4 activity, whereas studies with fluvoxamine (a substrate of CYP2C19) were inconclusive due to lack of specificity. We conclude that normeperidine formation in human liver microsomes is mainly catalyzed by CYP2B6 and CYP3A4, with a minor contribution from CYP2C19. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/15319333/CYP2B6_CYP3A4_and_CYP2C19_are_responsible_for_the_in_vitro_N_demethylation_of_meperidine_in_human_liver_microsomes_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=15319333 DB - PRIME DP - Unbound Medicine ER -