Kornhuber J, Retz W, Riederer P
Department of Psychiatry, University of Würzburg, Federal Republic of Germany.
J Neural Transm Suppl. 1995;46:315-23.
The mechanism of therapeutic latency of antidepressant and neuroleptic drugs is not clearly understood. Current hypotheses include slow adaptive processes after fast access to primary drug targets. Here, we present a hypothesis explaining therapeutic latency by slow accumulation of the drugs in acidic intracellular compartments. We have studied the pharmacokinetics of amantadine, a lysosomotropic model substance. It's fast therapeutic response is mediated by fast access to cell surface receptors. However, it slowly accumulates intracellularly in human brain tissue. Half-maximal and plateau concentrations are reached after 8 and at least 70 days of treatment, respectively. The concentration in brain tissue relative to CSF and serum is about 20:1. The high storage capacity of brain tissue is probably related to lysosomotropic properties of amantadine. This means that amantadine, as other lysosomotropic substances, is trapped by protonation in acidic intracellular compartments and may disturb biochemical processes that require an acidic milieu, such as the proton-driven transport of monoamines into synaptic vesicles. The mean daily oral dose of amantadine is low compared to the high storage capacity of brain and other tissues thus explaining the slow accumulation. Many psychotropic drugs including antidepressant and neuroleptic substances also have lysosomotropic properties. A slow accumulation in brain tissue is therefore likely for many antidepressant and neuroleptic drugs and has been directly demonstrated for fluoxetine. While lysosomotropism alone is not a sufficient explanation for antidepressant or neuroleptic properties of a certain drug, it contributes to high storage capacity and slow accumulation in brain tissue and results in disturbances of several biochemical processes. Slow accumulation in brain tissue might be related to the therapeutic latency of neuroleptic and antidepressant drugs.
抗抑郁药和抗精神病药物的治疗潜伏期机制尚未完全明确。目前的假说包括在快速作用于主要药物靶点后出现的缓慢适应性过程。在此，我们提出一种假说，即通过药物在酸性细胞内区室中的缓慢积累来解释治疗潜伏期。我们研究了溶酶体亲和性模型物质金刚烷胺的药代动力学。其快速的治疗反应是通过快速作用于细胞表面受体介导的。然而，它在人脑组织中细胞内积累缓慢。分别在治疗8天和至少70天后达到半数最大浓度和平台浓度。脑组织相对于脑脊液和血清的浓度约为20:1。脑组织的高储存能力可能与金刚烷胺的溶酶体亲和性有关。这意味着金刚烷胺与其他溶酶体亲和性物质一样，在酸性细胞内区室中因质子化而被困住，并可能干扰需要酸性环境的生化过程，例如质子驱动的单胺转运到突触小泡中。与脑和其他组织的高储存能力相比，金刚烷胺的平均每日口服剂量较低，因此解释了其缓慢积累的原因。许多精神药物，包括抗抑郁药和抗精神病药物，也具有溶酶体亲和性。因此，许多抗抑郁药和抗精神病药物在脑组织中可能积累缓慢，并且已经直接证明氟西汀存在这种情况。虽然仅溶酶体亲和性不足以解释某种药物的抗抑郁或抗精神病特性，但它有助于提高在脑组织中的储存能力和缓慢积累，并导致几种生化过程受到干扰。脑组织中的缓慢积累可能与抗精神病药物和抗抑郁药物的治疗潜伏期有关。
