Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Cracow, Poland.
Department of Pharmacobiology, Jagiellonian University Medical College, 9 Medyczna Street, 30-688, Cracow, Poland.
Naunyn Schmiedebergs Arch Pharmacol. 2018 Jan;391(1):37-49. doi: 10.1007/s00210-017-1431-y. Epub 2017 Oct 27.
The effect of some antidepressants co-administered with EMD386088 in the modified forced swim test in rats was investigated. Additionally, the pharmacokinetics, metabolic stability, and the effect of EMD386088 on P450 cytochromes were determined. Intraperitoneal (i.p.) coadministration of EMD386088 (2.5 mg/kg) and imipramine (15 mg/kg), reboxetine (5 mg/kg), moclobemide (10 mg/kg), or bupropion (10 mg/kg) evoked significant antidepressant-like activity, whereas no effect was observed after joint administration of EMD386088 with s-citalopram (10 mg/kg). Pharmacokinetic in vivo investigation showed a rapid absorption of EMD386088 (2.5 and 5 mg/kg) with t = 67 min (t = 5 min). Large volume of distribution (V /F = 102 L/kg) indicated its penetration into peripheral compartments. The most active coadministration of EMD386088 (2.5 mg/kg) with imipramine (15 mg/kg) resulted in slower absorption of the compound (C = 60 min) and decrease in the volume of distribution (V /F = 32.2 L/kg). EMD386088 penetrates the blood-brain barrier with a high brain/plasma ratio of about 19 (2.5 mg/kg) and 7.5 for coadministration with imipramine. The in silico and in vitro studies on EMD386088 metabolic stability showed the dehydrogenation of tetrahydropyridine moiety as its main metabolic pathway. EMD386088 did not influence on CYP3A4 activity, and it has been classified as a very weak CYP2D6 inhibitor (IC = 2.25 μM). The results obtained from the forced swim test in rats indicate that an activation of 5HT receptor may facilitate antidepressant-like activity of some antidepressants. The pharmacokinetic results suggest that the interaction between EMD386088 and imipramine could not have been pharmacokinetic in nature.
研究了在大鼠改良强迫游泳试验中与 EMD386088 同时给药的一些抗抑郁药的作用。此外，还测定了 EMD386088 的药代动力学、代谢稳定性以及对 P450 细胞色素的影响。腹腔（i.p.）给予 EMD386088（2.5mg/kg）和丙咪嗪（15mg/kg）、瑞波西汀（5mg/kg）、莫氯贝胺（10mg/kg）或安非他酮（10mg/kg）联合给药可引起明显的抗抑郁样作用，而 EMD386088 与西酞普兰（10mg/kg）联合给药则无作用。体内药代动力学研究表明，EMD386088（2.5 和 5mg/kg）吸收迅速，t = 67min（t = 5min）。大的分布容积（V/F = 102L/kg）表明其渗透到外周隔室。EMD386088 与丙咪嗪（15mg/kg）的最有效联合给药导致化合物吸收减慢（C = 60min）和分布容积降低（V/F = 32.2L/kg）。EMD386088 以约 19（2.5mg/kg）和与丙咪嗪联合给药时 7.5 的高脑/血浆比穿透血脑屏障。EMD386088 代谢稳定性的计算和体外研究表明，四氢吡啶部分的脱氢是其主要的代谢途径。EMD386088 不影响 CYP3A4 活性，被分类为非常弱的 CYP2D6 抑制剂（IC = 2.25μM）。大鼠强迫游泳试验的结果表明，5HT 受体的激活可能促进某些抗抑郁药的抗抑郁样作用。药代动力学结果表明，EMD386088 与丙咪嗪之间的相互作用不可能具有药代动力学性质。
