Department of Pharmacy, CNS Drug Delivery and Barrier Modelling group (CNSBM), University of Copenhagen, Copenhagen, Denmark.
Department of Pharmacy, Translational Pharmacokinetics/Pharmacodynamics group (tPKPD), Uppsala University, Uppsala, Sweden.
J Headache Pain. 2024 Oct 30;25(1):187. doi: 10.1186/s10194-024-01894-0.
BACKGROUND: Triptans are potent 5-HT receptor agonists used in migraine therapy, thought to act through peripheral mechanisms. It remains unclear whether triptans cross the blood-brain barrier (BBB) sufficiently to stimulate central 5-HT receptors. This study investigates the disposition of eletriptan and sumatriptan in central nervous system (CNS) and peripheral nervous system (PNS) regions and predicts regional 5-HT receptor occupancies at clinically relevant concentrations. METHODS: Using the Combinatory Mapping Approach (CMA) for regions of interest (ROI), we assessed the unbound tissue-to-plasma concentration ratio (K) in rats at steady state across CNS (hypothalamus, brain stem, cerebellum, frontal cortex, parietal cortex, striatum, hippocampus, whole brain, and spinal cord) and PNS (trigeminal ganglion and sciatic nerve) regions. We used K values to estimate unbound target-site concentrations and 5-HT receptor occupancies in humans. RESULTS: We observed heterogenous triptan transport across CNS and PNS regions with the highest extent of unbound drug transport across the blood-nerve barrier in the trigeminal ganglion (K: eletriptan: 0.519, and sumatriptan: 0.923). Both drugs displayed restricted entry across the BBB (K: eletriptan: 0.058, and sumatriptan: 0.045) combined with high inter-regional variability. We estimated near-complete receptor occupancy in the trigeminal ganglion, while lower occupancies were observed in the whole brain, irrespective of the drug or receptor subtype. For instance, eletriptan was predicted to achieve 84% 5-HT receptor occupancy in the trigeminal ganglion and 37% in the whole brain at clinically relevant concentrations. CONCLUSIONS: This study suggests that despite low BBB transport, both eletriptan and sumatriptan achieve unbound concentrations sufficient to stimulate 5-HT 5-HT, and 5-HT receptors not only in the trigeminal ganglion, but also in the CNS. Further research is needed to determine whether central mechanisms contribute to triptan's antimigraine effect and/or side effects.
背景：曲坦类药物是一种有效的 5-HT 受体激动剂，用于偏头痛的治疗，其作用机制被认为是通过外周机制发挥作用。曲坦类药物是否能充分穿透血脑屏障（BBB）以刺激中枢 5-HT 受体仍不清楚。本研究旨在探讨依来曲普坦和舒马曲普坦在中枢神经系统（CNS）和外周神经系统（PNS）区域的分布情况，并预测在临床相关浓度下，这些药物对中枢 5-HT 受体的占有率。
方法：使用组合映射方法（CMA）对感兴趣区域（ROI）进行评估，我们在大鼠处于稳定状态时，评估了中枢神经系统（下丘脑、脑干、小脑、额叶皮质、顶叶皮质、纹状体、海马体、全脑和脊髓）和外周神经系统（三叉神经节和坐骨神经）各区域的未结合组织与血浆浓度比（K）。我们使用 K 值来估计人类的未结合靶位浓度和 5-HT 受体占有率。
结果：我们观察到曲坦类药物在中枢神经系统和外周神经系统各区域的转运具有异质性，其中三叉神经节的未结合药物转运程度最高（K：依来曲普坦：0.519，舒马曲普坦：0.923）。两种药物均显示出对 BBB 的有限通透性（K：依来曲普坦：0.058，舒马曲普坦：0.045），同时伴有高的区域间变异性。我们估计在三叉神经节中几乎完全占据了受体，而在整个大脑中观察到较低的占有率，这与药物或受体亚型无关。例如，依来曲普坦在临床上相关的浓度下，预计在三叉神经节中达到 84%的 5-HT 受体占有率，而在全脑中达到 37%。
结论：本研究表明，尽管穿透 BBB 的能力较低，但依来曲普坦和舒马曲普坦都能达到足以刺激 5-HT 1B/1D 和 5-HT 受体的未结合浓度，这些受体不仅存在于三叉神经节中，也存在于中枢神经系统中。需要进一步的研究来确定中枢机制是否有助于曲坦类药物的抗偏头痛作用和/或副作用。
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