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The Active Glucuronide Metabolite of the Brain Protectant IMM-H004 with Poor Blood–Brain Barrier Permeability Demonstrates a High Partition in the Rat Brain via Multiple Mechanisms.

Authors :
Jiang, Jianwei
Luo, Lijun
Zhang, Ziqian
Liu, Xiao
Chen, Naihong
Li, Yan
Sheng, Li
Source :
Pharmaceutics. Mar2024, Vol. 16 Issue 3, p330. 21p.
Publication Year :
2024

Abstract

Background: Glucuronidation is an essential metabolic pathway for a variety of drugs. IMM-H004 is a novel neuroprotective agent against ischemic stroke, and its glucuronide metabolite IMM-H004G exhibits similar pharmacological activity. Despite possessing a higher molecular weight and polarity, brain exposure of IMM-H004G is much higher than that of IMM-H004. This study aimed to investigate the brain metabolism and transport mechanisms of IMM-H004 and IMM-H004G. Methods: First, the possibility of IMM-H004 glucuronidation in the brain was evaluated in several human brain cell lines and rat homogenate. Subsequently, the blood–brain barrier carrier-mediated transport mechanism of IMM-H004 and IMM-H004G was studied using overexpression cell models. In addition, intracerebroventricular injection, in situ brain perfusion model, and microdialysis/microinjection techniques were performed to study the distribution profiles of IMM-H004 and IMM-H004G. Results: IMM-H004 could be metabolized to IMM-H004G in both rat brain and HEB cells mediated by UGT1A7. However, IMM-H004G could not be hydrolyzed back into IMM-H004. Furthermore, the entry and efflux of IMM-H004 in the brain were mediated by the pyrilamine-sensitive H+/OC antiporter and P-gp, respectively, while the transport of IMM-H004G from the blood to the brain was facilitated by OATP1A2 and OATP2B1. Ultimately, stronger concentration gradients and OATP-mediated uptake played a critical role in promoting greater brain exposure of IMM-H004G. Conclusions: The active glucuronide metabolite of the brain protectant IMM-H004 with poor blood–brain barrier permeability demonstrates a high partition in the rat brain via multiple mechanisms, and our findings deepen the understanding of the mechanisms underlying the blood–brain barrier metabolism and transport of active glucuronide conjugates. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
19994923
Volume :
16
Issue :
3
Database :
Academic Search Index
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
176367855
Full Text :
https://doi.org/10.3390/pharmaceutics16030330