Wanwimolruk S, Levy G
Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, Amherst 14260.
J Pharm Sci. 1987 Jul;76(7):503-7. doi: 10.1002/jps.2600760702.
The purpose of this investigation was to determine the effect of age on the sensitivity of the central nervous system (CNS) to the depressant action of phenobarbital and ethanol. For this purpose, one or the other of these drugs was administered by slow iv infusion to male rats of various ages until the animals lost their righting reflex. The drug concentrations at that time in serum, brain, and cerebrospinal fluid were determined. The results obtained in studies on 1, 9, and 18-month-old Sprague-Dawley rats and on 7, 16, and 24-month-old Fischer-344 rats showed that phenobarbital concentrations at the pharmacologic end-point decreased with increasing age, indicative of an increased sensitivity of older animals to the CNS depressant effect of the barbiturate. Similar studies with ethanol on Sprague-Dawley rats (only) showed substantially higher drug concentrations at all sampling sites in 5-week-old animals than in 9- and 12-month-old animals at the onset of loss of righting reflex, but no significant differences between the 9- and 12-month-old groups. This investigation, which was designed to exclude or account for pharmacokinetic variables and to avoid confounding secondary effects, such as hypothermia and development of acute functional tolerance, showed a substantial increase in CNS sensitivity to phenobarbital and ethanol with increasing age in rats between the age of 1 and 9 months, and a less pronounced increase (phenobarbital) or no significant change (ethanol) in rats between 9 and 18 months of age.
本研究的目的是确定年龄对中枢神经系统（CNS）对苯巴比妥和乙醇抑制作用敏感性的影响。为此，通过缓慢静脉输注将这两种药物之一给予不同年龄的雄性大鼠，直至动物失去翻正反射。测定此时血清、脑和脑脊液中的药物浓度。在对1、9和18月龄的斯普拉格-道利大鼠以及7、16和24月龄的费希尔-344大鼠的研究中获得的结果表明，在药理学终点时苯巴比妥浓度随年龄增长而降低，这表明老年动物对巴比妥类药物的中枢神经系统抑制作用敏感性增加。仅对斯普拉格-道利大鼠进行的乙醇类似研究表明，在翻正反射消失开始时，5周龄动物所有采样部位的药物浓度显著高于9和12月龄动物，但9和12月龄组之间无显著差异。本研究旨在排除或考虑药代动力学变量，并避免混淆诸如体温过低和急性功能耐受性发展等次要效应，结果表明，1至9月龄大鼠中枢神经系统对苯巴比妥和乙醇的敏感性随年龄增长显著增加，而9至18月龄大鼠的增加不太明显（苯巴比妥）或无显著变化（乙醇）。
