Jelic P, Shih M F, Taberner P V
Department of Pharmacology, The Medical School, University of Bristol, UK.
Psychopharmacology (Berl). 1998 Jul;138(2):143-50. doi: 10.1007/s002130050656.
Diurnal variation in blood and plasma ethanol levels (BACs) has been observed in animals undergoing chronic ethanol treatment, but the information available is insufficient to determine whether the different patterns seen are due to differences in ethanol administration schedules or to strain of the animal. In this study, we have compared plasma ethanol levels in males of two mouse strains with no innate preference for ethanol, TO and CBA, during two commonly employed chronic ethanol treatment schedules. Ethanol was administered in solution as sole drink (CED) (10% or 20% w/v ethanol) for 4 weeks, or in liquid diet form (ELD), (3.5% w/v ethanol for 2 days, then 7% for 5 days). Mice were housed eight per cage on a 12-h light cycle (0900-2100 hours). Plasma ethanol concentration was monitored over the 24-h period. Activity of liver alcohol dehydrogenase (ADH) was measured between 0900 and 1100 hours. CBA mice showed greater variability in body weights than TO mice, which weighed more throughout the period of study and had significantly higher total energy intakes. TO mice consumed more ELD than CBA mice. Following an initial 2-day period of 3.5% ELD, both strains decreased their diet intake when ethanol content of the diet was increased to 7% w/v, which resulted in weight loss. Mice on the CED schedules decreased their fluid intake with increasing concentration of ethanol in the drinking solution. Highest daily ethanol intakes were observed in mice on ELD (19.1 +/- 1.7 and 22.2 +/- 0.6 g/kg body weight in CBA and TO mice, respectively). Marked diurnal variation in plasma ethanol levels was observed, which was dependent on the treatment schedule, strain and method of ethanol administration. Highest levels were found in mice on the ELD schedule (104.8 +/- 7.7 mM in CBA mice, 113.5 +/- 14.5 mM in TO mice), peaking at 1900 and at 0900 hours in CBA and TO mice, respectively. Lower plasma ethanol concentrations were reached in mice on the CED schedules, peaking at midnight (34.6 +/- 8.1 mM and 35.4 +/- 8.8 mM in CBA and TO mice on 20% CED, respectively, and 3.7 +/- 1.2 mM and 6.6 +/- 2.1 mM in CBA and TO mice on 10% CED). Naive CBA mice had slightly higher liver ADH activity as compared to their TO counterparts. No effect of 10% CED on liver ADH activity was found in either mouse strain. In conclusion, we have confirmed the importance of monitoring plasma ethanol levels during chronic treatment, as there is marked diurnal variation, dependent on the light/dark cycle. Factors such as strain of the animal and the method of delivery of ethanol are also important, whereas liver ADH plays a minor role. Monitoring the daily ethanol consumption is insufficient to predict the resulting plasma levels of the drug.
在接受慢性乙醇处理的动物中已观察到血液和血浆乙醇水平（BACs）的昼夜变化，但现有信息不足以确定所观察到的不同模式是由于乙醇给药方案的差异还是动物品系的差异。在本研究中，我们比较了两种对乙醇无先天偏好的小鼠品系（TO和CBA）的雄性小鼠在两种常用的慢性乙醇处理方案下的血浆乙醇水平。乙醇以溶液形式作为唯一饮品（CED）（10%或20% w/v乙醇）给予4周，或以液体饮食形式（ELD）（3.5% w/v乙醇持续2天，然后7%持续5天）给予。小鼠每笼饲养8只，采用12小时光照周期（09:00 - 21:00）。在24小时期间监测血浆乙醇浓度。在09:00至11:00之间测量肝脏乙醇脱氢酶（ADH）的活性。CBA小鼠的体重变化比TO小鼠更大，TO小鼠在整个研究期间体重更重，总能量摄入量显著更高。TO小鼠比CBA小鼠消耗更多的ELD。在最初3.5% ELD的2天期间后，当饮食中的乙醇含量增加到7% w/v时，两个品系的小鼠饮食摄入量均减少，导致体重减轻。采用CED方案的小鼠随着饮用溶液中乙醇浓度的增加而减少液体摄入量。在ELD方案下的小鼠中观察到最高的每日乙醇摄入量（CBA和TO小鼠分别为19.1±1.7和22.2±0.6 g/kg体重）。观察到血浆乙醇水平有明显的昼夜变化，这取决于处理方案、品系和乙醇给药方法。在ELD方案下的小鼠中发现最高水平（CBA小鼠为104.8±7.7 mM，TO小鼠为113.5±14.5 mM），分别在CBA和TO小鼠的19:00和09:00达到峰值。采用CED方案的小鼠血浆乙醇浓度较低，在午夜达到峰值（20% CED的CBA和TO小鼠分别为34.6±8.1 mM和35.4±8.8 mM，10% CED的CBA和TO小鼠分别为3.7±1.2 mM和6.6±2.1 mM）。未处理的CBA小鼠的肝脏ADH活性与其TO对应物相比略高。在两种小鼠品系中均未发现10% CED对肝脏ADH活性有影响。总之，我们证实了在慢性治疗期间监测血浆乙醇水平的重要性，因为存在明显的昼夜变化，这取决于光/暗周期。动物品系和乙醇给药方法等因素也很重要，而肝脏ADH起的作用较小。监测每日乙醇消耗量不足以预测药物的血浆水平。
