Wood Martyn D, Scott Claire, Clarke Kirsten, Westaway Julie, Davies Ceri H, Reavill Charlie, Hill Mark, Rourke Claire, Newson Michael, Jones Declan N C, Forbes Ian T, Gribble Andrew
Psychiatry Centre for Excellence in Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.
Eur J Pharmacol. 2006 Sep 28;546(1-3):88-94. doi: 10.1016/j.ejphar.2006.07.008. Epub 2006 Jul 21.
Aripiprazole is a novel antipsychotic drug, which displays partial agonist activity at the dopamine D(2) receptor. Aripiprazole has been extensively studied pre-clinically, both in vitro and in vivo, and these results have been correlated with clinical findings. However, aripiprazole is metabolised differently in rats and man and these metabolites may contribute to the profile of aripiprazole observed in vivo. We have therefore studied the interaction of aripiprazole and its principal rat and human metabolites in both in vitro models of dopamine hD(2) receptor function and affinity, and of in vivo models of dopamine rat D(2) receptor function. The human metabolite displayed similar levels of partial agonist activity to aripiprazole at the dopamine hD(2) receptor and displayed similar behavioural profile to aripiprazole in vivo, suggesting that in man the metabolite may maintain the effects of aripiprazole. In contrast, the rat metabolite displayed antagonist activity both in vitro and in vivo. Thus care must be taken in ascribing effects seen in vivo with aripiprazole in rats to dopamine D(2) receptor partial agonist activity in man, and that care must also be taken in extrapolating effects seen in rats to man, particularly from long-term studies.
阿立哌唑是一种新型抗精神病药物，它在多巴胺D(2)受体上表现出部分激动剂活性。阿立哌唑已在临床前进行了广泛的体外和体内研究，这些结果已与临床发现相关联。然而，阿立哌唑在大鼠和人体内的代谢方式不同，这些代谢产物可能有助于解释在体内观察到的阿立哌唑的特征。因此，我们研究了阿立哌唑及其主要大鼠和人类代谢产物在多巴胺hD(2)受体功能和亲和力的体外模型以及多巴胺大鼠D(2)受体功能的体内模型中的相互作用。人类代谢产物在多巴胺hD(2)受体上表现出与阿立哌唑相似水平的部分激动剂活性，并且在体内表现出与阿立哌唑相似的行为特征，这表明在人体内该代谢产物可能维持阿立哌唑的作用。相比之下，大鼠代谢产物在体外和体内均表现出拮抗剂活性。因此，在将阿立哌唑在大鼠体内观察到的效应归因于人类多巴胺D(2)受体部分激动剂活性时必须谨慎，并且在将大鼠中观察到的效应外推至人类时也必须谨慎，尤其是在长期研究中。
