Doctor of Philosophy
The goal of this project was to investigate the effect of input-rate (oral and intravenous) and degree of exposure on the pharmacokinetics of ethanol and on subjective and objective measures of impairment, as well as on the development of acute tolerance to the effects of ethanol in young, healthy volunteers.
The primary objective of this research was to test the following hypotheses: 1) the rate and degree of ethanol exposure (oral and intravenous) in normal healthy males and females affect the pharrnacokinetics (PK) and pharmacodynarnics (PD) of ethanol in a non-linear fashion; 2) the EEG changes after ethanol administration correlate with changes in psychometric performance and subject-rated impairment, as well as serum ethanol concentrations; and 3) acute tolerance develops to the subjective effects of ethanol which is not reflected in changes in electroencephalographic (EEG) activity or psychometric performance.
This study was conducted in two parts. Part I was a five-way crossover pilot study in six healthy male volunteers to evaluate the effect of dose and dose-rate on the PK and PD of ethanol. This study evaluated changes in EEG activity, psychometric performance and subjective impairment to evaluate the relationship between these subjective and objective measures, and the relationship between these measures and serum ethanol concentrations. Part II was a 4-way crossover study in 16 healthy male and female subjects to study the PK-PD relationship for intravenous (IV) ethanol and acute tolerance development to the effects of ethanol. In this study, subjects were administered individualized intravenous ethanol infusions, to achieve a target concentration of 1000 mg/L after different durations of exposure. This study was designed to i:nvestigate the PK of ethanol, as well as to assess changes in EEG activity, psychometric performance and subjective impairment. This study evaluated the relationship between these measures, and the relationship between these measures and serum ethanol concentrations, as well as the development of acute tolerance to the effects of ethanol.
Results from both studies showed that: 1) Ethanol, after oral and intravenous administration, follows capacity-limited pharmacokinetics. Intrinsic PK parameters, V max• Km and Vd were independent of dose and input-rate, but were associated with fairly high inter-individual variability. 2) Ethanol, after oral and intravenous administration, induced a transient slowing of the EEG and impairment in psychometric performance. The magnitude of the changes in these measures appeared to be dose-related as well as inputrate- related (observed in the IV study), however there was a fairly large degree of variability in response between individuals. 3) Ethanol, after oral and intravenous administration, induced transient subjective impairment, which was dose-related and input-rate-related, and correlated with serum ethanol concentrations across treatments. 4) A subset of subjects (2/6 males in the oral ethanol study, and 2/8 males and 4/8 female subjects in the IV study) were classified as "non-responders" based on their lack of subjective response to ethanol, despite serum ethanol concentrations, psychometric impairment and EEG changes that were consistent with the other subjects. 5) There was significant exposure-related acute tolerance development to the subjective effects of ethanol observed in both studies. This acute tolerance development could be characterized by a PK-PD model incorporating tolerance as a compensatory feedback mechanism to counter-regulate the direct subjective impairment effect of the drug. Acute tolerance was not observed for the psychometric impairment or changes in EEG activity, indicating that there was a temporal disparity be~een objective and subjective impairment following ethanol administration. 6) The EEG changes were not correlated with the psychometric or subjective impairment. 7) There was a significant gender difference observed in the Cmax and Vdss for ethanol, probably due to gender differences in body weight and body water content. There was also a significant gender difference observed in the magnitude of ethanol-induced subjective impairment, with females showing a lower degree of subjective impairment, despite achieving similar concentrations and demonstrating similar psychometric impairment and EEG changes. This gender difference may be partly confounded by the larger proportion of female "non-responders" compared to the male "non-responders" in the study.
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