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Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes.
Drug Metab Dispos. 1997 Mar; 25(3):390-3.DM

Abstract

The specificities of orphenadrine and methimazole on eight human liver P450 enzyme activities were evaluated by studying the extent of inhibition at different concentrations in two protocols: competitive inhibition and preincubation. In the competitive inhibition protocol, orphenadrine decreased CYP2B6 marker activity up to 45-57% in human liver microsomes and up to 80-97% in cell microsomes containing cDNA-expressed CYP2B6. Orphenadrine strongly decreased CYP2D6 marker activity by 80-90%. Orphenadrine also partially decreased the CYP1A2, CYP2A6, CYP3A4, and CYP2C19 marker activities. In the preincubation protocol, orphenadrine decreased the CYP2B6 activity in cDNA-expressed cell microsomes to completion. In human liver microsomes, orphenadrine strongly decreased the marker activities of CYP2B6, CYP2D6, as well as CYP2C9; and partially decreased the marker activities of CYP1A2, CYP2A6, CYP3A4, and CYP2C19. In the competitive inhibition protocol, methimazole had no effect on the marker activities of CYP2E1 and CYP2A6; slightly decreased CYP2D6 marker activity; partially decreased the marker activities of CYP2C19, CYP2C9, and CYP2B6; and dramatically decreased CYP3A4 marker activity. Methimazole decreased CYP1A2 marker activity at lower concentrations, but not at the highest concentration studied (1 mM). In the preincubation protocol, methimazole was shown to be a potent and nonspecific inhibitor of all the enzyme activities. Marker activities of CYP2C9, CYP2C19, and CYP3A4 were completely inhibited at relatively low concentrations. This study indicates orphenadrine cannot be used as a selective inhibitor of CYP2B6 in human liver microsomes and that methimazole is not a selective inhibitor of the flavin-containing monooxygenase in human liver microsomes.

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Publisher Full Text

Authors+Show Affiliations

Guo Z
Department of Drug Metabolism and Pharmacokinetics, Rhone-Poulenc Rorer, Collegeville, PA 19426, USA.
Raeissi S
No affiliation info available
White RB
No affiliation info available
Stevens JC
No affiliation info available

MeSH

Antiparkinson AgentsAntithyroid AgentsBinding, CompetitiveCytochrome P-450 Enzyme InhibitorsCytochrome P-450 Enzyme SystemEnzyme InhibitorsHumansIsoenzymesMethimazoleMicrosomes, LiverOrphenadrineSensitivity and Specificity

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9172960

Citation

Guo, Z, et al. "Orphenadrine and Methimazole Inhibit Multiple Cytochrome P450 Enzymes in Human Liver Microsomes." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 25, no. 3, 1997, pp. 390-3.
Guo Z, Raeissi S, White RB, et al. Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metab Dispos. 1997;25(3):390-3.
Guo, Z., Raeissi, S., White, R. B., & Stevens, J. C. (1997). Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 25(3), 390-3.
Guo Z, et al. Orphenadrine and Methimazole Inhibit Multiple Cytochrome P450 Enzymes in Human Liver Microsomes. Drug Metab Dispos. 1997;25(3):390-3. PubMed PMID: 9172960.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes. AU - Guo,Z, AU - Raeissi,S, AU - White,R B, AU - Stevens,J C, PY - 1997/3/1/pubmed PY - 1997/3/1/medline PY - 1997/3/1/entrez SP - 390 EP - 3 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 25 IS - 3 N2 - The specificities of orphenadrine and methimazole on eight human liver P450 enzyme activities were evaluated by studying the extent of inhibition at different concentrations in two protocols: competitive inhibition and preincubation. In the competitive inhibition protocol, orphenadrine decreased CYP2B6 marker activity up to 45-57% in human liver microsomes and up to 80-97% in cell microsomes containing cDNA-expressed CYP2B6. Orphenadrine strongly decreased CYP2D6 marker activity by 80-90%. Orphenadrine also partially decreased the CYP1A2, CYP2A6, CYP3A4, and CYP2C19 marker activities. In the preincubation protocol, orphenadrine decreased the CYP2B6 activity in cDNA-expressed cell microsomes to completion. In human liver microsomes, orphenadrine strongly decreased the marker activities of CYP2B6, CYP2D6, as well as CYP2C9; and partially decreased the marker activities of CYP1A2, CYP2A6, CYP3A4, and CYP2C19. In the competitive inhibition protocol, methimazole had no effect on the marker activities of CYP2E1 and CYP2A6; slightly decreased CYP2D6 marker activity; partially decreased the marker activities of CYP2C19, CYP2C9, and CYP2B6; and dramatically decreased CYP3A4 marker activity. Methimazole decreased CYP1A2 marker activity at lower concentrations, but not at the highest concentration studied (1 mM). In the preincubation protocol, methimazole was shown to be a potent and nonspecific inhibitor of all the enzyme activities. Marker activities of CYP2C9, CYP2C19, and CYP3A4 were completely inhibited at relatively low concentrations. This study indicates orphenadrine cannot be used as a selective inhibitor of CYP2B6 in human liver microsomes and that methimazole is not a selective inhibitor of the flavin-containing monooxygenase in human liver microsomes. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/9172960/Orphenadrine_and_methimazole_inhibit_multiple_cytochrome_P450_enzymes_in_human_liver_microsomes_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9172960 DB - PRIME DP - Unbound Medicine ER -