Intravenous Ethanol Infusions Can Mimic the Time Course of Breath Alcohol Concentrations Following Oral Alcohol Administration in Healthy Volunteers
Version of Record online: 11 MAR 2009
Copyright © 2009 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 33, Issue 5, pages 938–944, May 2009
How to Cite
Ramchandani, V. A., Plawecki, M., Li, T.-K. and O’Connor, S. (2009), Intravenous Ethanol Infusions Can Mimic the Time Course of Breath Alcohol Concentrations Following Oral Alcohol Administration in Healthy Volunteers. Alcoholism: Clinical and Experimental Research, 33: 938–944. doi: 10.1111/j.1530-0277.2009.00906.x
- Issue online: 13 APR 2009
- Version of Record online: 11 MAR 2009
- Received for publication April 2, 2008; accepted January 2, 2009.
- Alcohol Clamp;
- Route of Administration;
- Physiologically-Based Pharmacokinetic Model;
- Pharmacokinetic Variability;
- Healthy Social Drinkers;
- Breath Alcohol Concentration
Background: Our previous studies have used intravenous (IV) clamping methods to demonstrate that family history positive (FHP) subjects exhibit a greater initial response to alcohol than family history negative (FHN) subjects. These results differ from other studies of family history of alcoholism (FHA) influences, most of which have used an oral alcohol challenge, suggesting that the route of administration may influence both the response to alcohol and FHA-related differences in response. To examine this possibility, one approach would be to directly compare responses following oral and IV alcohol administration in the same subjects. There is, however, a 3- to 4-fold variance, between- and within-subjects, in the breath alcohol concentrations (BrACs) following oral alcohol administration. Thus, our objective was to characterize the between-subject variability in the time course of BrACs following oral alcohol administration in healthy volunteers and to develop an IV infusion method to mimic the BrAC-time course attained following oral alcohol in the same subject.
Methods: This was a 2-session study in young adult, healthy, nondependent drinkers. In the first session, subjects ingested an oral dose of alcohol, based on total body water, to achieve a target peak BrAC of 80 mg%. In the second session, subjects received an IV infusion of ethanol designed to achieve the same BrAC time course as that achieved in the first session. The individualized infusion-rate profile was precomputed using a physiologically-based pharmacokinetic (PBPK) model for alcohol with model parameters adjusted to the individual’s physiology. The peak BrACs (Cmax), times of peak BrAC (Tmax), and the areas under the BrAC vs. time curve (AUC) were compared between sessions to assess how closely the BrAC exposure during the IV infusion session mimicked the exposure following oral alcohol.
Results: The time course of BrACs following oral alcohol administration showed a high degree of between-subject variability. Mean Cmax, Tmax, and AUC did not differ by gender, indicating that calculation of oral doses based on total body water results in comparable BrAC-time courses, on average, for females and males. The IV infusion driven BrAC-time profiles demonstrated good fidelity to the BrAC-time curves resulting from oral alcohol: the mean %difference in Cmax and AUC were both 11%, while the mean %difference for Tmax was 27%. This degree of variability is less than half that seen across individuals following oral alcohol administration, which was substantial [coefficient of variation (%CV) ranging from 22 to 52%].
Conclusions: Despite the use of standardized doses and controlled experimental conditions, there was substantial between-subject variability in the BrAC time course following oral administration of alcohol. The PBPK-model-based infusion method can mimic the BrACs attained with oral alcohol for individual subjects. This method provides a platform to evaluate effects attributable to the route of administration on the response to alcohol, as well as the influence of determinants such as family history of alcoholism on the alcohol response.