JPET Assistant Professor of Medicine (Clinician-Educator)

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Störmer, E.
Right arrow Articles by Greenblatt, D. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Störmer, E.
Right arrow Articles by Greenblatt, D. J.

Vol. 295, Issue 2, 793-801, November 2000

Scaling Drug Biotransformation Data from cDNA-Expressed Cytochrome P-450 to Human Liver: A Comparison of Relative Activity Factors and Human Liver Abundance in Studies of Mirtazapine Metabolism1

Elke Störmer2, Lisa L. von Moltke and David J. Greenblatt

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts

The present study represents a comparison of three approaches to transform recombinant cytochrome P-450 (rCYP) enzyme kinetic data to human liver activity using mirtazapine (MIR) biotransformation as a model. MIR metabolite rCYP formation rates were corrected using I) relative activity factors (RAFs) determined on site, II) RAFs based on activity data provided by the rCYP manufacturer, and III) immunologically determined human liver abundance of CYP isoforms reported in the literature. For 2.5, 25, and 250 µM MIR, predictions of 1) the relative contribution of CYP isoforms to a particular reaction, 2) absolute metabolite formation rates, 3) the relative contribution of each pathway to net MIR biotransformation, and 4) the relative contribution of CYP isoforms to net MIR biotransformation were generated, and the results were compared with data obtained with human liver microsomes (HLM). We found that RAFs determined on site most accurately predict the results observed in HLM. Estimations based on liver abundance systematically underestimated CYP1A2 and overestimated CYP3A and CYP2C9 contributions to MIR metabolism and, therefore, seem less suitable to predict CYP isoform involvement in a particular reaction. Normalized RAFs calculated from the manufacturer activity data fell within the range of RAFs determined on site and lead to similar results for CYP isoform contribution to metabolic reactions and to net MIR biotransformation. Considering the time and resource-intensive step of RAF determination, manufacturer RAFs are an alternative to RAFs determined on site for the transformation of rCYP enzyme kinetic data; both of them provide more accurate estimations than immunologically determined human liver CYP isoform content.

1 This work was supported by Grants MH-34223, MH-01237, and DA-05258 from the U.S. Department of Health and Human Services.

2 Recipient of an HSP III doctoral grant by the German Academic Exchange Service (DAAD).

0022-3565/00/2952-0793$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
X.-Q. Li, L. Weidolf, R. Simonsson, and T. B. Andersson
Enantiomer/Enantiomer Interactions between the S- and R- Isomers of Omeprazole in Human Cytochrome P450 Enzymes: Major Role of CYP2C19 and CYP3A4
J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 777 - 787.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
A. Galetin, C. Brown, D. Hallifax, K. Ito, and J. B. Houston
UTILITY OF RECOMBINANT ENZYME KINETICS IN PREDICTION OF HUMAN CLEARANCE: IMPACT OF VARIABILITY, CYP3A5, AND CYP2C19 ON CYP3A4 PROBE SUBSTRATES
Drug Metab. Dispos., December 1, 2004; 32(12): 1411 - 1420.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
D. Springer, L. D. Paul, R. F. Staack, T. Kraemer, and H. H. Maurer
IDENTIFICATION OF CYTOCHROME P450 ENZYMES INVOLVED IN THE METABOLISM OF 4'-METHYL-{alpha}-PYRROLIDINOPROPIOPHENONE, A NOVEL SCHEDULED DESIGNER DRUG, IN HUMAN LIVER MICROSOMES
Drug Metab. Dispos., August 1, 2003; 31(8): 979 - 982.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
T. D. Bjornsson, J. T. Callaghan, H. J. Einolf, V. Fischer, L. Gan, S. Grimm, J. Kao, S. P. King, G. Miwa, L. Ni, et al.
THE CONDUCT OF IN VITRO AND IN VIVO DRUG-DRUG INTERACTION STUDIES: A PHARMACEUTICAL RESEARCH AND MANUFACTURERS OF AMERICA (PhRMA) PERSPECTIVE
Drug Metab. Dispos., July 1, 2003; 31(7): 815 - 832.
[Abstract] [Full Text] [PDF]

Home page
 J Clin PharmacolHome page
T. D. Bjornsson, J. T. Callaghan, H. J. Einolf, V. Fischer, L. Gan, S. Grimm, J. Kao, S. P. King, G. Miwa, L. Ni, et al.
The Conduct of In Vitro and In Vivo Drug-Drug Interaction Studies: A PhRMA Perspective
J. Clin. Pharmacol., May 1, 2003; 43(5): 443 - 469.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
L. L. von Moltke, D. J. Greenblatt, G. M. Giancarlo, B. W. Granda, J. S. Harmatz, and R. I. Shader
Escitalopram (S-Citalopram) and Its Metabolites in Vitro: Cytochromes Mediating Biotransformation, Inhibitory Effects, and Comparison to R-Citalopram
Drug Metab. Dispos., August 1, 2001; 29(8): 1102 - 1109.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
K. Venkatakrishnan, L. L. von Moltke, M. H. Court, J. S. Harmatz, C. L. Crespi, and D. J. Greenblatt
Comparison between Cytochrome P450 (CYP) Content and Relative Activity Approaches to Scaling from cDNA-Expressed CYPs to Human Liver Microsomes: Ratios of Accessory Proteins as Sources of Discrepancies between the Approaches
Drug Metab. Dispos., April 13, 2001; 28(12): 1493 - 1504.
[Abstract] [Full Text]

Home page
 J. Pharmacol. Exp. Ther.Home page
K. Venkatakrishnan, L. L. von Moltke, and D. J. Greenblatt
Application of the Relative Activity Factor Approach in Scaling from Heterologously Expressed Cytochromes P450 to Human Liver Microsomes: Studies on Amitriptyline as a Model Substrate
J. Pharmacol. Exp. Ther., April 1, 2001; 297(1): 326 - 337.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2000 by the American Society for Pharmacology and Experimental Therapeutics.