Dalla Christina, Pavlidi Pavlina, Sakelliadou Danai-Georgia, Grammatikopoulou Tatiana, Kokras Nikolaos
Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
First Department of Psychiatry, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Front Behav Neurosci. 2022 May 23;16:844916. doi: 10.3389/fnbeh.2022.844916. eCollection 2022.
Treatment of neuropsychiatric disorders relies on the effective delivery of therapeutic molecules to the target organ, the brain. The blood-brain barrier (BBB) hinders such delivery and proteins acting as transporters actively regulate the influx and importantly the efflux of both endo- and xeno-biotics (including medicines). Neuropsychiatric disorders are also characterized by important sex differences, and accumulating evidence supports sex differences in the pharmacokinetics and pharmacodynamics of many drugs that act on the brain. In this minireview we gather preclinical and clinical findings on how sex and sex hormones can influence the activity of those BBB transporter systems and affect the brain pharmacokinetics of psychotropic medicines. It emerges that it is not well understood which psychotropics are substrates for each of the many and not well-studied brain transporters. Indeed, most evidence originates from studies performed in peripheral tissues, such as the liver and the kidneys. None withstanding, accumulated evidence supports the existence of several sex differences in expression and activity of transport proteins, and a further modulating role of gonadal hormones. It is proposed that a closer study of sex differences in the active influx and efflux of psychotropics from the brain may provide a better understanding of sex-dependent brain pharmacokinetics and pharmacodynamics of psychotropic medicines.
神经精神疾病的治疗依赖于将治疗分子有效递送至靶器官——大脑。血脑屏障（BBB）阻碍了这种递送，而作为转运体的蛋白质会积极调节内源性和外源性物质（包括药物）的流入，尤其是流出。神经精神疾病还具有显著的性别差异，越来越多的证据支持许多作用于大脑的药物在药代动力学和药效学方面存在性别差异。在这篇综述中，我们收集了关于性别和性激素如何影响血脑屏障转运体系统活性以及影响精神药物脑药代动力学的临床前和临床研究结果。目前尚不清楚众多研究较少的脑转运体中，每种转运体的精神药物底物是什么。实际上，大多数证据来自在肝脏和肾脏等外周组织中进行的研究。尽管如此，积累的证据支持转运蛋白在表达和活性方面存在若干性别差异，以及性腺激素的进一步调节作用。有人提出，深入研究精神药物从大脑的主动流入和流出中的性别差异，可能有助于更好地理解精神药物的性别依赖性脑药代动力学和药效学。
