A comparison of plasma alprazolam concentrations following different routes of chronic administration in the Sprague-Dawley rat: implications for psychotropic drug research.
A comparison of plasma alprazolam concentrations following different routes of chronic administration in the Sprague-Dawley rat: implications for psychotropic drug research.
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斯普拉格-道利大鼠不同慢性给药途径后血浆阿普唑仑浓度的比较：对精神药物研究的影响。
DOI：
10.1007/s002130000469
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发表时间：
2000
影响因子：
3.4
通讯作者：
Owens,MJ
中科院分区：
文献类型：
--
作者：
Skelton,KH;Nemeroff,CB;Owens,MJ
理由：苯二氮卓类药物对长时间的焦虑症治疗有效。这导致在一天的过程中相对稳定的血浆浓度。然而，由于大鼠的药物清除率存在差异，它们通常比人类更快地代谢和清除药物，因此很难在大鼠中建立这种稳定水平的模型。目的：对几种慢性阿普唑仑给药方法进行比较，以确定哪种方法最能产生可重复的、治疗相关的药物水平。方法：雄性Sprague-Dawley大鼠分别通过Alzet 2ML2渗透微型泵和市售缓释微丸两种皮下途径给予阿普唑仑1周和2周。此外，将阿普唑仑与市售的液体脂肪乳化饮食混合，口服2周。使用硅胶植入物递送几种不同的苯二氮卓类药物也在体外进行了评估。结果：阿普唑仑经渗透小泵每日2 mg/kg给药7 d后，10只同剂量大鼠血药浓度范围为<1 ~ 97 ng/ml。缓释微丸产生更一致的血浆浓度，但只有最低限度的有效提高血浆浓度。在体外研究中，在6厘米的管道中使用含有90毫克药物的硅胶植入物显示，阿普唑仑的稳定释放量仅为45-55µg/天，而安定的稳定释放量为625-650µg/天。与这些方法相反，将阿普唑仑纳入市售的液体饮食（~25 - 150mg /kg /天）可使阿普唑仑及其代谢物的血浆浓度在适合模拟临床暴露的范围内出现一致的剂量依赖性增加。结论：这些发现表明，产生可重复的、临床相关的、大鼠之间一致的阿普唑仑血浆浓度的最有效技术是将药物掺入液体饮食中。这些发现可能对确定其他苯二氮卓类药物或精神药物的给药途径也有价值。
Rationale:Benzodiazepines are effective in the treatment of anxiety disorders over a prolonged period of time. This results in relatively stable plasma concentrations over the course of a day. However, due to differences in drug clearance in rats, which generally metabolize and clear drugs much more rapidly than humans, it is difficult to model this steady level in rats.Objectives:Several methods of chronic alprazolam administration were compared to determine which would best result in reproducible, therapeutically relevant levels of the drug.Methods:Male Sprague-Dawley rats were administered alprazolam via two subcutaneous routes, Alzet 2ML2 osmotic minipumps and commercially produced slow-release pellets, for 1 week and 2 weeks, respectively. Additionally, alprazolam was orally administered for 2 weeks by mixing the compound into a commercially available liquid, fat emulsion-based diet. The use of silastic implants to deliver several different benzodiazepines was also evaluated in vitro.Results:Following 7 days of alprazolam administration at 2 mg/kg per day via osmotic minipump, plasma concentrations in ten identically treated rats ranged from <1 ng/ml to 97 ng/ml. Slow-release pellets produced more consistent plasma concentrations, but were only minimally effective at raising plasma concentrations. In vitro studies utilizing silastic implants containing 90 mg drug in 6 cm of tubing revealed stable release of only 45–55 µg/day alprazolam versus 625–650 µg/day diazepam. In contrast to these methodologies, incorporation of alprazolam into a commercially available liquid diet (~25–150 mg/kg per day) provided consistent, dose-dependent increases in plasma concentrations of alprazolam and its metabolites in a range appropriate for mimicking clinical exposure.Conclusions:These findings indicate that the most effective technique to produce plasma concentrations of alprazolam that are reproducible, clinically pertinent, and consistent between rats is to incorporate the drug into a liquid diet. These findings may also be of value in determining dosing routes for other benzodiazepines or psychotropic drugs.