Pharmacokinetics of m-chlorophenylpiperazine after intravenous and oral administration in healthy male volunteers:: Implication for the pharmacodynamic profile
Pharmacokinetics of m-chlorophenylpiperazine after intravenous and oral administration in healthy male volunteers:: Implication for the pharmacodynamic profile
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DOI：
10.1055/s-2004-827175
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发表时间：
2004-07-01
影响因子：
4.3
通讯作者：
Rao, ML
中科院分区：
文献类型：
--
作者：
Feuchtl, A;Bagli, M;Rao, ML
简介： 血清素在精神疾病中发挥着重要作用，尤其是在抑郁和焦虑中。已经描述了七种不同的主要血清素受体亚型。人们一直在寻找受体选择性激动剂和拮抗剂，以找到合适的药物来测试体内受体敏感性。不同的血清素受体亚型参与神经内分泌功能的控制。间氯苯基哌嗪 (mCPP) 作为血清素 2C、IA、IB 和 1 D 受体亚型的激动剂，用于激发试验。本研究的目的是开发一个药代动力学-药效模型来描述 mCPP 对垂体激素分泌的影响。方法：对 12 名健康男性静脉注射和口服 mCPP 后测定激素和 mCPP 血浆浓度。将 mCPP 的动力学参数与药物对激素反应的影响进行比较。结果：mCPP 治疗后，与安慰剂相比，ACTH、皮质醇和催乳素水平显着升高。临床反应也显着增加（焦虑、颤抖、头晕、对光和噪音的敏感性增强以及害怕失去控制）。静脉输注后最大 mCPP 浓度变化 2.3 倍，口服给药后变化 8 倍。绝对生物利用度范围为12%至84%。 mCPP的消除半衰期在静脉输注后为2.4小时至6.8小时，口服后为2.6小时至6.1小时。然而，动力学数据以及药效学反应的变化在一定程度上排除了药代动力学-药效学建模。 mCPP 处置动力学的广泛个体差异不能完全用 mCPP 代谢酶细胞色素 P4502D6 的遗传变异来解释，该变异在所有先证者中均已测定。讨论：本研究中不能排除导致处置动力学变异的其他因素，这表明 mCPP 不是测试体内 5-羟色胺 2C 受体活性的合适模型药物。
introduction: Serotonin plays an important role in psychiatric diseases, most notably in depression and anxiety. Seven different major serotonin receptor subtypes have been described. Receptor-selective agonists and antagonists have been searched for to find a suitable drug to test the in vivo receptor-sensitivity. Different serotonin receptor subtypes take part in the control of neuroendocrine function. m-Chlorophenylpiperazine (mCPP) acts as an agonist to serotonin 2C, I A, I B, and 1 D receptor subtypes and is applied in challenge tests. The object of this study was to develop a pharmacokinetic-pharmacodynamic model to describe the effects of mCPP on pituitary hormone secretion. Methods: The hormone and mCPP plasma concentrations were determined after intravenous and oral administration of mCPP to 12 healthy men. The kinetic parameters of mCPP were compared to the drug's effect on hormonal response. Results: After mCPP treatment, ACTH, cortisol, and prolactin levels were significantly increased compared to placebo. There was also a significant in-crease in clinical response (anxiety, shivering, dizziness, heightened sensitivity toward light and noise, and fear of losing control). Maximum mCPP concentrations varied 2.3-fold after intravenous infusion and 8-fold after oral administration. The absolute bioavailability ranged from 12% to 84%. mCPP's elimination half-life ranged from 2.4 h to 6.8 h after intravenous infusion and from 2.6 h to 6.1 h after oral application. However, the kinetic data as well as the pharmacodynamic response varied to an extent that precluded pharmacokinetic-pharmacodynamic modeling. The wide interindividual variability in mCPP's disposition kinetics could not be fully explained by genetic variation of the mCPP-metabolizing enzyme cytochrome P4502D6, which was determined in all probands. Discussion: Other factors contributing to the variability in disposition kinetics could not be ruled out in this study, suggesting that mCPP is not a suitable model drug to test serotonin 2C receptor activity in vivo.