Intravenous Ethanol Infusions Can Mimic the Time Course of Breath Alcohol Concentrations Following Oral Alcohol Administration in Healthy Volunteers
Intravenous Ethanol Infusions Can Mimic the Time Course of Breath Alcohol Concentrations Following Oral Alcohol Administration in Healthy Volunteers
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DOI：
10.1111/j.1530-0277.2009.00906.x
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发表时间：
2009-05-01
影响因子：
3.2
通讯作者：
O'Connor, Sean
中科院分区：
文献类型：
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作者：
Ramchandani, Vijay A.;Plawecki, Martin;O'Connor, Sean
我们以前的研究使用静脉(IV)钳制方法证明，家族史阳性(FHP)受试者比家族史阴性(FHN)受试者对酒精的初始反应更大。这些结果不同于其他关于酒精中毒家族史(FHA)影响的研究，这些研究大多使用口服酒精挑战，这表明给药途径可能既影响对酒精的反应，也可能影响与FHA相关的反应差异。为了检查这种可能性，一种方法是直接比较相同受试者口服和静脉注射酒精后的反应。然而，在口服酒精后，受试者之间和受试者内部的呼气酒精浓度(Brac)存在3到4倍的差异。因此，我们的目标是描述健康志愿者口服酒精后BrAC的时间进程的受试者之间的变异性，并开发一种静脉输注方法来模拟同一受试者口服酒精后获得的BRAC时间进程。这是一项针对年轻、健康、非依赖型饮酒者的为期两次的研究。在第一阶段，受试者以全身水分为基础，口服一定剂量的酒精，以达到80 mg%的目标峰值。在第二个疗程中，受试者接受了乙醇的静脉注射，目的是达到与第一个疗程相同的BRAC时间进程。使用基于生理的酒精药代动力学(PBPK)模型预先计算个性化输液速率分布，模型参数根据个体的生理进行调整。比较不同时段的BrAC峰值(C-max)、峰值时间(T-max)和BRAC-时间曲线下面积(AUC)，以评估在静脉输液过程中BRAC暴露与口服酒精后暴露有多接近。口服酒精后BrAC的时间进程在受试者之间表现出高度的变异性。平均C-max、T-max和AUC没有性别差异，这表明基于全身水分的口服剂量计算结果平均而言，女性和男性的呼吸时间进程是相似的。静脉输液驱动的制动时间曲线与口服酒精所致的制动时间曲线具有良好的保真度：C-max和AUC的平均%差值均为11%，而T-max的平均差值为27%。这种变异程度不到口服酒精后个体的一半，后者是相当大的[变异系数(%CV)从22%到52%]。尽管使用了标准剂量和受控的实验条件，但口服酒精后的BRAC时间进程在受试者之间存在显著的差异。基于PBPK模型的输液方法可以模拟个体受试者口服酒精所获得的BRAC。这种方法提供了一个平台来评估给药途径对酒精反应的影响，以及诸如酗酒家族史等决定因素对酒精反应的影响。
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.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 (C-max), times of peak BrAC (T-max), 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.The time course of BrACs following oral alcohol administration showed a high degree of between-subject variability. Mean C-max, T-max, 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 C-max and AUC were both 11%, while the mean %difference for T-max 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%].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.