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Effect of cimetidine on hepatic cytochrome P450: evidence for formation of a metabolite-intermediate complex.
Drug Metab Dispos. 1995 Dec; 23(12):1407-11.DM

Abstract

Cimetidine is an inhibitor of hepatic cytochrome P450 (CYP) in vivo and in vitro in both rats and humans. However, the concentrations of cimetidine required to inhibit drug metabolism in hepatic microsomes in vitro are 100-1000-fold higher than those associated with a similar degree of inhibition in vivo. Recently, we provided evidence indicating that cimetidine selectively inhibits CYP2C11 in the rat and that it acts by forming a metabolite-intermediate (MI) complex. To investigate this further, optical-difference spectroscopy was performed with the use of microsomes from uninduced and phenobarbital-induced male rats treated with cimetidine in vivo or, after a preincubation step, in vitro. In microsomes from uninduced rats treated with cimetidine in vivo or in vitro, a spectral peak at 428-430 nm was observed that was not dissociated by the addition of potassium ferricyanide. The spectral peak obtained with cimetidine in vitro was dependent on the presence of NADPH and on the concentration of cimetidine in the reaction mixture, indicating the presence of an MI complex. The magnitude of this complex was reduced in microsomes from phenobarbital induced rats that were administered cimetidine either in vivo or in vitro. The formation of the complex was also inhibited by preincubation of the microsomes with anti-rat CYP2C11 immunoglobulin. These results are consistent with the hypothesis that cimetidine inhibits CYP in vivo in the rat by forming an MI complex, largely with CYP2C11, and that this complex can be generated in vitro by incubating microsomes with cimetidine in the presence of NADPH.

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Authors+Show Affiliations

Levine M
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver.
Bellward GD
No affiliation info available

MeSH

AnimalsCimetidineCytochrome P-450 Enzyme SystemHistamine H2 AntagonistsLiverMaleNADPPhenobarbitalRatsRats, WistarSpectrometry, Fluorescence

Pub Type(s)

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

Language

eng

PubMed ID

8689952

Citation

Levine, M, and G D. Bellward. "Effect of Cimetidine On Hepatic Cytochrome P450: Evidence for Formation of a Metabolite-intermediate Complex." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 23, no. 12, 1995, pp. 1407-11.
Levine M, Bellward GD. Effect of cimetidine on hepatic cytochrome P450: evidence for formation of a metabolite-intermediate complex. Drug Metab Dispos. 1995;23(12):1407-11.
Levine, M., & Bellward, G. D. (1995). Effect of cimetidine on hepatic cytochrome P450: evidence for formation of a metabolite-intermediate complex. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 23(12), 1407-11.
Levine M, Bellward GD. Effect of Cimetidine On Hepatic Cytochrome P450: Evidence for Formation of a Metabolite-intermediate Complex. Drug Metab Dispos. 1995;23(12):1407-11. PubMed PMID: 8689952.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of cimetidine on hepatic cytochrome P450: evidence for formation of a metabolite-intermediate complex. AU - Levine,M, AU - Bellward,G D, PY - 1995/12/1/pubmed PY - 1995/12/1/medline PY - 1995/12/1/entrez SP - 1407 EP - 11 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 23 IS - 12 N2 - Cimetidine is an inhibitor of hepatic cytochrome P450 (CYP) in vivo and in vitro in both rats and humans. However, the concentrations of cimetidine required to inhibit drug metabolism in hepatic microsomes in vitro are 100-1000-fold higher than those associated with a similar degree of inhibition in vivo. Recently, we provided evidence indicating that cimetidine selectively inhibits CYP2C11 in the rat and that it acts by forming a metabolite-intermediate (MI) complex. To investigate this further, optical-difference spectroscopy was performed with the use of microsomes from uninduced and phenobarbital-induced male rats treated with cimetidine in vivo or, after a preincubation step, in vitro. In microsomes from uninduced rats treated with cimetidine in vivo or in vitro, a spectral peak at 428-430 nm was observed that was not dissociated by the addition of potassium ferricyanide. The spectral peak obtained with cimetidine in vitro was dependent on the presence of NADPH and on the concentration of cimetidine in the reaction mixture, indicating the presence of an MI complex. The magnitude of this complex was reduced in microsomes from phenobarbital induced rats that were administered cimetidine either in vivo or in vitro. The formation of the complex was also inhibited by preincubation of the microsomes with anti-rat CYP2C11 immunoglobulin. These results are consistent with the hypothesis that cimetidine inhibits CYP in vivo in the rat by forming an MI complex, largely with CYP2C11, and that this complex can be generated in vitro by incubating microsomes with cimetidine in the presence of NADPH. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/8689952/Effect_of_cimetidine_on_hepatic_cytochrome_P450:_evidence_for_formation_of_a_metabolite_intermediate_complex_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8689952 DB - PRIME DP - Unbound Medicine ER -