Regional Distribution of Unbound Eletriptan and Sumatriptan in the CNS and PNS in Rats: Implications for a Potential Central Action

Overview

Journal J Headache Pain

Publisher Biomed Central

Date 2024 Oct 31

PMID 39478486

Authors

Nana Svane

Frida Ballgren

Aghavni Ginosyan

Mie Kristensen

Birger Brodin

Irena Loryan

Affiliations

Soon will be listed here.

Abstract

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.

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