Effect of chronic infusion of olanzapine and clozapine on food intake and body weight gain in male and female rats
Effect of chronic infusion of olanzapine and clozapine on food intake and body weight gain in male and female rats
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DOI：
10.1016/j.lfs.2007.08.009
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发表时间：
2007-09-01
期刊：
影响因子：
6.1
通讯作者：
Fernstrom, John D.
中科院分区：
文献类型：
--
作者：
Choi, SuJean;DiSilvio, Briana;Fernstrom, John D.
许多抗精神病药物在每日注射一次或两次时会导致人类体重增加，但通常不会使大鼠体重增加。由于与人类相比，抗精神病药物在大鼠体内的血液半衰期较短，可能需要通过持续输注来长期给药，才能看到大鼠体重持续增加。将雄性和雌性大鼠植入微型泵，持续输注奥氮平（5毫克/千克/天）、氯氮平（10毫克/千克/天）或赋形剂，持续11天。测量食物摄入量和体重；通过高效液相色谱法测量血液药物浓度。奥氮平增加了雌性大鼠的食物摄入量和体重，但对雄性大鼠没有影响。血清奥氮平浓度为30 - 35纳克/毫升。氯氮平对雌性或雄性大鼠的食物摄入量或体重没有影响。血清氯氮平浓度约为75纳克/毫升。单剂量药代动力学分析显示，每种药物的血清末端半衰期为1.2 - 1.5小时，无性别差异。尽管奥氮平和氯氮平会促进人类体重增加，但这些药物似乎对大鼠的体重和食物摄入量影响极小，除了奥氮平对雌性大鼠有适度影响外，即使在慢性输注期间血清中达到了奥氮平的治疗水平。因此，先前研究中单次给药后药物的快速清除不能解释抗精神病药物对该物种体重增加的微弱影响或无影响。因此，大鼠似乎不是某些抗精神病药物在人类中导致体重增加的合适模型。（C）2007爱思唯尔公司。保留所有权利。
Many antipsychotics cause weight gain in humans, but usually not in rats, when injected once or twice daily. Since blood antipsychotic half-lives are short in rats, compared to humans, chronic administration by constant infusion may be necessary to see consistent weight gain in rats. Male and female rats were implanted with mini-pumps for constant infusion of olanzapine (5 mg/kg/day), clozapine (10 mg/kg/day) or vehicle for 11 days. Food intake and body weight were measured; blood drug levels were measured by HPLC. Olanzapine increased food intake and body weight in female, but not male rats. Serum olanzapine concentrations were 30-35 ng/ml. Clozapine had no effect on food intake or body weight in female or male rats. Serum clozapine concentrations were about 75 ng/ml. Single-dose pharmacokinetic analysis revealed a serum terminal half-life of 1.2-1.5 h for each drug, with no sex differences. Despite the fact that olanzapine and clozapine promote weight gain in humans, these drugs appear to have minimal effects on body weight and food intake in rats, except for a modest effect of olanzapine in female rats, even though therapeutic levels of olanzapine are achieved in serum during chronic infusion. Hence, the rapid clearance of drug following single administration in previous studies cannot explain the weak or absent effects of antipsychotics on weight gain in this species. The rat thus appears to be an inadequate model of weight gain produced by some antipsychotics in humans. (C) 2007 Elsevier Inc. All rights reserved.