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ToxSci Advance Access published online on February 16, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi120
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Toxicological Sciences © The Author [2005]. Published by Oxford University Press [on behalf of the Society of Toxicology]. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received October 26, 2004
Accepted February 12, 2005

Biotransformation and Toxicokinetics

INCORPORATION OF THERAPEUTIC INTERVENTIONS IN PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING OF HUMAN CLINICAL CASE REPORTS OF ACCIDENTAL OR INTENTIONAL OVERDOSING WITH ETHYLENE GLYCOL

R.A. Corley 1* and K.E. McMartin 2

1 Battelle Pacific Northwest Division, Richland, WA 99352, USA
2 Louisiana State University Health Sciences Center, Shreveport, LA, USA

* To whom correspondence should be addressed.
R.A. Corley, E-mail: rick.corley{at}pnl.gov


  Abstract

Although occupational uses of the HPV chemical, ethylene glycol, have not been associated with adverse effects, there are case reports where humans have either intentionally or accidentally ingested large quantities of ethylene glycol, primarily from antifreeze. The acute toxicity of ethylene glycol can proceed through three stages, each associated with a different metabolite: central nervous system depression (ethylene glycol), cardiopulmonary effects associated with metabolic acidosis (glycolic acid) and ultimately renal toxicity (oxalic acid), depending upon the total amounts consumed and effectiveness of therapeutic interventions. A physiologically based pharmacokinetic (PBPK) model developed in a companion paper (Corley et al., 2005) was refined in this study to include clinically relevant treatment regimens for ethylene glycol poisoning such as hemodialysis or metabolic inhibition with either ethanol or fomepizole. Such modifications enabled the model to describe data from several human case reports confirming the ability of the previous model to describe the pharmacokinetics of ethylene glycol and its metabolite, glycolic acid, in humans across a broad range of doses and multiple exposure routes. By integrating the case report data sets with controlled studies in this PBPK model, it was demonstrated that fomepizole, if administered early enough in a clinical situation, can be more effective than ethanol or hemodialysis in preventing the metabolism of ethylene glycol to more toxic metabolites. Hemodialysis remains an important option, however, if treatment is instituted after a significant amount of EG is metabolized or if renal toxicity has occurred.

Keywords: Ethylene glycol; glycolic acid; PBPK modeling; fomepizole; ehanol; hemodialysis.
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