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The effect of cimetidine on dextromethorphan O-demethylase activity of human liver microsomes and recombinant CYP2D6.
Drug Metab Dispos. 2004 Apr; 32(4):460-7.DM

Abstract

Clinically, cimetidine therapy impairs the clearance of various drugs metabolized by CYP2D6, such as desipramine and sparteine. Cimetidine is known to reversibly inhibit CYP2D6 in vitro; however, Ki values are greater than plasma concentrations observed in vivo. There is evidence suggesting that this drug may act as an inactivator of cytochrome P450 (P450) enzymes after metabolic activation. Therefore, the purpose of this study was to determine whether cimetidine acts as a mechanism-based inactivator of CYP2D6. Dextromethorphan O-demethylation was used as a probe of CYP2D6 activity. The Vmax and Km of this reaction were 0.82 +/- 0.06 nmol/min/nmol of P450 and 4.1 +/- 0.1 microM, respectively, in pooled human liver microsomes; and 15.9 +/- 0.8 nmol/min/nmol P450 and 1.4 +/- 0.6 microM, respectively, with recombinant CYP2D6. With human liver microsomes, cimetidine competitively inhibited CYP2D6 (Ki = 38 +/- 5 microM) and was a mixed inhibitor of recombinant CYP2D6 (Ki = 103 +/- 17 microM). Preincubation of human liver microsomes with cimetidine and NADPH did not increase the inhibitory potency of cimetidine; however, preincubation with recombinant CYP2D6 resulted in enzyme inactivation that could be attenuated by the CYP2D6 inhibitor quinidine. The KI and kinact were estimated to be 77 microM and 0.03 min-1, respectively, and the half-life of inactivation was 25 min. Therefore, cimetidine may represent a class of compounds capable of inactivating specific cytochromes P450 in vivo, but for which conditions may not be achievable in vitro using human liver microsomes.

Authors+Show Affiliations

Faculty of Pharmaceutical Sciences, the University of British Columbia, Vancouver, British Columbia, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16680870

Citation

Madeira, Maria, et al. "The Effect of Cimetidine On Dextromethorphan O-demethylase Activity of Human Liver Microsomes and Recombinant CYP2D6." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 32, no. 4, 2004, pp. 460-7.
Madeira M, Levine M, Chang TK, et al. The effect of cimetidine on dextromethorphan O-demethylase activity of human liver microsomes and recombinant CYP2D6. Drug Metab Dispos. 2004;32(4):460-7.
Madeira, M., Levine, M., Chang, T. K., Mirfazaelian, A., & Bellward, G. D. (2004). The effect of cimetidine on dextromethorphan O-demethylase activity of human liver microsomes and recombinant CYP2D6. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 32(4), 460-7.
Madeira M, et al. The Effect of Cimetidine On Dextromethorphan O-demethylase Activity of Human Liver Microsomes and Recombinant CYP2D6. Drug Metab Dispos. 2004;32(4):460-7. PubMed PMID: 16680870.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The effect of cimetidine on dextromethorphan O-demethylase activity of human liver microsomes and recombinant CYP2D6. AU - Madeira,Maria, AU - Levine,Marc, AU - Chang,Thomas K H, AU - Mirfazaelian,Ahmad, AU - Bellward,Gail D, PY - 2006/5/10/pubmed PY - 2006/5/11/medline PY - 2006/5/10/entrez SP - 460 EP - 7 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 32 IS - 4 N2 - Clinically, cimetidine therapy impairs the clearance of various drugs metabolized by CYP2D6, such as desipramine and sparteine. Cimetidine is known to reversibly inhibit CYP2D6 in vitro; however, Ki values are greater than plasma concentrations observed in vivo. There is evidence suggesting that this drug may act as an inactivator of cytochrome P450 (P450) enzymes after metabolic activation. Therefore, the purpose of this study was to determine whether cimetidine acts as a mechanism-based inactivator of CYP2D6. Dextromethorphan O-demethylation was used as a probe of CYP2D6 activity. The Vmax and Km of this reaction were 0.82 +/- 0.06 nmol/min/nmol of P450 and 4.1 +/- 0.1 microM, respectively, in pooled human liver microsomes; and 15.9 +/- 0.8 nmol/min/nmol P450 and 1.4 +/- 0.6 microM, respectively, with recombinant CYP2D6. With human liver microsomes, cimetidine competitively inhibited CYP2D6 (Ki = 38 +/- 5 microM) and was a mixed inhibitor of recombinant CYP2D6 (Ki = 103 +/- 17 microM). Preincubation of human liver microsomes with cimetidine and NADPH did not increase the inhibitory potency of cimetidine; however, preincubation with recombinant CYP2D6 resulted in enzyme inactivation that could be attenuated by the CYP2D6 inhibitor quinidine. The KI and kinact were estimated to be 77 microM and 0.03 min-1, respectively, and the half-life of inactivation was 25 min. Therefore, cimetidine may represent a class of compounds capable of inactivating specific cytochromes P450 in vivo, but for which conditions may not be achievable in vitro using human liver microsomes. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/16680870/The_effect_of_cimetidine_on_dextromethorphan_O_demethylase_activity_of_human_liver_microsomes_and_recombinant_CYP2D6_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16680870 DB - PRIME DP - Unbound Medicine ER -