Skip Navigation



ToxSci Advance Access published online on January 12, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh057
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
78/1/20    most recent
kfh057v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
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 Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Sultatos, L. G.
Right arrow Articles by Flynn, E. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sultatos, L. G.
Right arrow Articles by Flynn, E. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Received September 10, 2003; accepted November 15, 2003
© 2004 Society of Toxicology

Biotransformation and Toxicokinetics

Incorporation of the Genetic Control of Alcohol Dehydrogenase into a Physiologically Based Pharmacokinetic Model for Ethanol in Humans

Lester G. Sultatos 1*, Gina M. Pastino 2, Clint A. Rosenfeld 1, and Edward J. Flynn 1

1 Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103
2 Schering-Plough Research Institute, P.O. Box 32, 144 Route 94, Lafayette, NJ 07843

* To whom correspondence should be addressed. E-mail: sultatle{at}umdnj.edu.


  Abstract

The assessment of the variability of human responses to foreign chemicals is an important step in characterizing the public health risks posed by non-therapeutic hazardous chemicals, as well as the risk of encountering adverse reactions with drugs. Of the many sources of interindividual variability in chemical response so far identified, hereditary factors are some of the least understood. Physiologically based pharmacokinetic modeling linked with Monte Carlo sampling has been shown to be a useful tool for quantification of interindividual variability in chemical disposition and/or response when applied to biological processes that displayed single genetic polymorphisms. The current report has extended this approach by modeling the complex hereditary control of alcohol dehydrogenase, which includes polygenic control, as well as polymorphisms at two allelic sites, and by assessing the functional significance of this hereditary control on ethanol disposition. The physiologically based pharmacokinetic model for ethanol indicated that peak blood ethanol levels and time to peak blood ethanol levels were marginally affected by alcohol dehydrogenase genotypes, with simulated subjects possessing the B2 subunit having slightly lower peak blood ethanol levels and shorter times to beak blood levels compared to subjects without the B2 subunit. In contrast, the area under the curve (AUC) of the ethanol blood decay curve was very sensitive to alcohol dehydrogenase genotype, with AUCs from any genotype including the ADH1B2 allele considerably smaller than AUCs from any genotype without the ADH1B2 allele. Furthermore, the AUCs in the ADH1C1/C1 genotype were moderately lower than the AUCs from the corresponding ADH1C2/C2 genotype. Moreover, these simulations demonstrated that interindividual variability of ethanol disposition is affected by alcohol dehydrogenase, and that the degree of this variability was a function of the ethanol dose.

Key Words: alcohol dehydrogenase, physiologically based pharmacokinetic modeling, ethanol, risk assessment .


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.