DMD Simcyp

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


     

Drug Metabolism and Disposition Fast Forward
First published on August 20, 2007; DOI: 10.1124/dmd.107.016816

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.107.016816v1
35/11/1990    most recent
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
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 Vuppugalla, R.
Right arrow Articles by Rodrigues, D. A
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vuppugalla, R.
Right arrow Articles by Rodrigues, D. A


Received for publication May 30, 2007.
Revised August 13, 2007.
Accepted for publication August 15, 2007.

EFFECT OF COMMONLY USED ORGANIC SOLVENTS ON THE KINETICS OF CYTOCHROME P450 2B6- AND 2C8-DEPENDENT ACTIVITY IN HUMAN LIVER MICROSOMES

Ragini Vuppugalla 1*, Shu-Ying Chang 1, Hongjian Zhang 1, Punit H Marathe 1, David A Rodrigues 1

1 Bristol-Myer's Squibb

* Address correspondence to: E-mail: ragini.vuppugalla{at}bms.com

Abstract

The effect of common organic solvents on the activities of various human cytochrome P450s has been reported. However, very little is known about their influence on CYP2B6 and CYP2C8 enzymes. The purpose of this study was to investigate the effect of solvents on the kinetics of a representative CYP2B6 (bupropion hydroxylase) and CYP2C8 (paclitaxel hydroxylase) reaction in human liver microsomes. Methanol, ethanol, dimethyl sulfoxide (DMSO), and acetonitrile were studied at increasing volumes (v/v). Acetonitrile, DMSO, and ethanol were shown to increase the Km and decrease the intrinsic clearance (CLint) of CYP2B6-mediated bupropion hydroxylation in a concentration-dependent manner. These solvents did not noticeably alter the Vmax at concentrations of ≤1% (v/v). Unlike the other solvents studied, the effect of methanol (≤0.5%, v/v) on CYP2B6 kinetics was negligible. Both DMSO and ethanol increased the Km and decreased the CLint of CYP2C8-mediated paclitaxel hydroxylation in a concentration-dependent manner. Acetonitrile had minimal influence on CYP2C8 enzyme kinetics at concentrations of ≤1% (v/v). Methanol decreased the Km of paclitaxel at low concentrations followed by an increase at concentrations of ≥2% (v/v). This differential influence on Km resulted in an increased CLint at low concentrations followed by a decrease at high concentrations. The studied solvents had minimal influence on Vmax of paclitaxel. Collectively, DMSO and ethanol were not suitable for characterizing CYP2B6- and CYP2C8-mediated reactions, as they demonstrated concentration-dependent inhibition. Methanol and acetonitrile at concentrations of ≤0.5% and ≤1%(v/v), appeared to be suitable for the measurement of CYP2B6- and CYP2C8-mediated activities, respectively.


Key words: CYP inhibition, CYP2B, CYP2C, cytochrome P450, enzyme kinetics, human CYP enzymes


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
A. J. Lau and T. K. H. Chang
Inhibition of Human CYP2B6-Catalyzed Bupropion Hydroxylation by Ginkgo biloba Extract: Effect of Terpene Trilactones and Flavonols
Drug Metab. Dispos., September 1, 2009; 37(9): 1931 - 1937.
[Abstract] [Full Text] [PDF]


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

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics.