Syrek M, Wójcikowski J, Daniel W A
Department of Pharmacokinetics and Drug Metabolism, Polish Academy of Sciences, Kraków, Poland.
Pol J Pharmacol. 1997 Nov-Dec;49(6):453-62.
The aim of the present study was to search for a possible effect of tricyclic antidepressants on the pharmacokinetics of promazine. Male Wistar rats received promazine and/or an antidepressant (amitriptyline, imipramine) at a dose of 10 mg/kg i.p. twice a day for two weeks. Amitriptyline increased the plasma concentrations of promazine and N-desmethylpromazine. The concentration of promazine sulfoxide was lowered after 30 min, but later it was raised after 6 and 12 h. The interaction was pronounced after 6 and 12 h when the concentration of promazine was 3 times as high, that of N-desmethylpromazine 25 times as high, and that of sulfoxide 22 times as high as those observed after administration of promazine alone. Similar results were obtained in the brain. Imipramine produced less distinct changes in promazine pharmacokinetics. It did not produce any significant changes in promazine concentration (a tendency to raise it after 30 min was observed) in plasma, but it significantly increased the concentration of N-desmethylpromazine and decreased that of promazine sulfoxide. Changes in the brain did not follow closely those in the plasma. In the brain, significant increases in the levels of promazine and its metabolites were observed after 6 and 12 h. In vitro studies with liver microsomes showed that chronic co-administration of the antidepressants did not significantly influence the rate of promazine demethylation and sulfoxidation. Instead, the Lineweaver-Burk's analysis showed that both amitriptyline and imipramine competitively inhibited the two metabolic pathways of the neuroleptic. The potency of imipramine to inhibit the promazine metabolism in vitro was lower than that of amitriptyline, which was in line with its weaker effect on the pharmacokinetics of promazine in vivo. The observed increase in the sum of concentrations of the measured compounds (promazine + metabolites) in the plasma suggests additional inhibition by amitriptyline of another, metabolic pathway of promazine (e.g. hydroxylation). It is concluded that amitriptyline and imipramine which interfere with the metabolism (and probably distribution) of promazine produce potent increases in the brain (in the case of amitriptyline also in the plasma) concentrations of the neuroleptic.
本研究的目的是探寻三环类抗抑郁药对丙嗪药代动力学可能产生的影响。雄性Wistar大鼠每天腹腔注射10mg/kg的丙嗪和/或一种抗抑郁药（阿米替林、丙咪嗪），持续两周，每天两次。阿米替林提高了丙嗪和N-去甲基丙嗪的血浆浓度。丙嗪亚砜的浓度在30分钟后降低，但在6小时和12小时后升高。在6小时和12小时时相互作用明显，此时丙嗪浓度是单独给予丙嗪后观察到浓度的3倍，N-去甲基丙嗪浓度是25倍，亚砜浓度是22倍。在大脑中也得到了类似结果。丙咪嗪对丙嗪药代动力学产生的变化不太明显。它在血浆中未使丙嗪浓度产生任何显著变化（仅在30分钟后有升高趋势），但显著提高了N-去甲基丙嗪的浓度并降低了丙嗪亚砜的浓度。大脑中的变化与血浆中的变化并非紧密相关。在大脑中，6小时和12小时后观察到丙嗪及其代谢物水平显著升高。对肝微粒体的体外研究表明，长期联合使用抗抑郁药并未显著影响丙嗪去甲基化和亚砜化的速率。相反，Lineweaver-Burk分析表明，阿米替林和丙咪嗪均竞争性抑制了该抗精神病药物的两条代谢途径。丙咪嗪在体外抑制丙嗪代谢的效力低于阿米替林，这与其在体内对丙嗪药代动力学的较弱影响一致。血浆中所测化合物（丙嗪+代谢物）浓度总和的增加表明，阿米替林对丙嗪的另一条代谢途径（如羟基化）有额外抑制作用。得出的结论是，干扰丙嗪代谢（可能还有分布）的阿米替林和丙咪嗪会使大脑中（阿米替林在血浆中也会）该抗精神病药物的浓度显著升高。
