Contribution of lysosomal trapping to the total tissue uptake of psychotropic drugs
Contribution of lysosomal trapping to the total tissue uptake of psychotropic drugs
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DOI：
10.1111/j.1600-0773.1997.tb00285.x
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发表时间：
1997-02-01
期刊：
影响因子：
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通讯作者：
Wojcikowski, J
中科院分区：
文献类型：
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作者：
Daniel, WA;Wojcikowski, J
本研究旨在评估磷脂结合和溶酶体捕获对丙嗪、丙咪嗪等不同化学结构的精神药物的组织总摄取的个体贡献。阿米替林、氟西汀、舍曲林(基本亲脂性药物)和卡马西平(亲脂性，但不是碱性)。我们还试图找出溶酶体捕获是否可能参与精神药物临床组合中的药代动力学相互作用。在大鼠不同组织的切片上进行了摄取实验，作为一个具有完整溶酶体的系统。每种药物的初始浓度为5微米，并将结果与存在溶酶体抑制剂、氯化铵或莫能菌素的情况下得到的结果进行比较。基本的亲脂性精神药物在以溶酶体丰富著称的组织中表现出高摄取率，主要是肺部。药物积累量最高的是异丙嗪和阿米替林。“溶酶体抑制剂”显著减少了基本亲脂性药物的摄取，特别是在肺和肝脏。阿米替林、丙咪嗪和丙嗪的作用最强，大脑中有中等程度的碱性亲脂性精神药物积聚，只有阿米替林才有显著的溶酶体抑制剂作用。丙咪嗪和舍曲林。上述规律的唯一例外是丙咪嗪和舍曲林，它们被脂肪组织比肺或肝脏等富含溶酶体的组织更广泛地摄取。卡马西平也未表现出溶酶体嗜性。阿米替林和异丙嗪相互减少肺切片对阿米替林的摄取，当药物在氯化铵存在下共同孵育时，不发生相互作用。综上所述，研究结果表明：(1)溶酶体捕捉剂是决定碱性亲脂性精神药物分布的一个重要因素；(2)它们的组织摄取更多地依赖于磷脂结合而不是溶酶体捕捉剂；(3)溶酶体捕捉剂可能参与了药物之间的药代动力学相互作用。
The present study was aimed at assessing individual contributions of the phospholipid binding and lysosomal trapping to the total tissue uptake of psychotropic drugs with different chemical structures, such as promazine, imipramine. amitriptyline, fluoxetine, sertraline (basic lipophilic drugs) and carbamazepine (lipophilic, but not basic). We also tried to find out whether lysosomal trapping may be involved in the pharmacokinetic interactions in clinical combinations of psychotropics. Uptake experiments were carried out on slices of various rat tissues as a system with intact lysosomes. Initial concentration of each drug was 5 mu M. The results were compared with those obtained in the presence of the ''lysosomal inhibitors'', ammonium chloride or monensin. The basic lipophilic psychotropics showed high uptake in tissues known for the abundance of lysosomes, mainly the lungs. The highest drug accumulation was;as found for promazine and amitriptyline. ''Lysosomal inhibitors' significantly decreased the uptake of the basic lipophilic drugs, particularly in the lungs and liver. The most potent effect was observed for amitriptyline, imipramine and promazine, The brain showed moderate accumulation of basic lipophilic psychotropics and the effect of the ''lysosomal inhibitors'' was significant only in the case of amitriptyline. imipramine and sertraline. The only exception to the above regularity were imipramine and sertraline which were taken up more extensively by the adipose tissue than by lysosome-rich tissues such as the lungs or liver. Carbamazepine did nor show lysosomotropism. Amitriptyline and promazine mutually decreased their uptake by lung slices when the drugs were incubated jointly In the presence of ammonium chloride the interaction did not occur. In conclusion, the obtained results show that (1) the lysosomal trapping is an important factor determining the distribution of the basic lipophilic psychotropics: however (2) their tissue uptake depends more on the phospholipid binding than on the lysosomal trapping: (3) the lysosomal trapping may be involved in the pharmacokinetic interactions between psychotropics.