Feuchtl A, Bagli M, Stephan R, Frahnert C, Kölsch H, Kühn K U, Rao M L
Department of Psychiatry, University of Bonn, Germany.
Pharmacopsychiatry. 2004 Jul;37(4):180-8. doi: 10.1055/s-2004-827175.
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, 1A, 1B, and 1D 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.
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.
After mCPP treatment, ACTH, cortisol, and prolactin levels were significantly increased compared to placebo. There was also a significant increase 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.
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.
血清素在精神疾病中发挥着重要作用，尤其是在抑郁症和焦虑症方面。已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，以找到一种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。间氯苯哌嗪（mCPP）作为血清素2C、1A、1B和1D受体亚型的激动剂，用于激发试验。本研究的目的是建立一个药代动力学-药效学模型，以描述mCPP对垂体激素分泌的影响。
对12名健康男性静脉内和口服给予mCPP后，测定激素和mCPP的血浆浓度。将mCPP的动力学参数与药物对激素反应的影响进行比较。
与安慰剂相比，mCPP治疗后促肾上腺皮质激素、皮质醇和催乳素水平显著升高。临床反应（焦虑、颤抖、头晕、对光和噪音的敏感性增加以及害怕失去控制）也显著增加。静脉输注后mCPP的最大浓度变化了2.3倍，口服后变化了8倍。绝对生物利用度范围为12%至84%。静脉输注后mCPP的消除半衰期为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程度使得药代动力学-药效学建模无法进行。在所有受试者中测定的mCPP代谢酶细胞色素P4502D6的基因变异无法完全解释mCPP处置动力学的个体间广泛差异。
本研究无法排除其他导致处置动力学变异性的因素，这表明mCPP不是在体内测试血清素2C受体活性的合适模型药物。
