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Purpose <p>Hypoxic–ischemic (HI) brain injury results in death and lifelong disabilities in newborns. Pharmaceutical agents are not available to treat HI brain injury. We reported that intraperitoneal (IP) BRT_002 is neuroprotective after HI in neonatal rodents. We examined whether intranasal (IN) BRT_002 provides adequate exposure by measuring plasma/brain PK, brain distribution, brain-to-plasma ratios, and hemispheric volume loss after HI, and compared results to our published findings after IP administration.</p> Methods <p>Metabolic stability of BRT_002 and its metabolite BRT_001 was examined in rat and human liver microsomes. Postnatal day P7 sham or HI-exposed rats given IN BRT_002 (30&#xa0;mg/kg) had plasma and ipsilateral brain BRT_002/BRT_001 quantified by LC–MS/MS at 1, 2, 6, and 24&#xa0;h along with PK parameters (C<sub>max</sub>, AUC<sub>tot</sub>, t<sub>1/2</sub>) and brain-to-plasma ratios derived. IN BRT_002 was given at 0, 24, and 48&#xa0;h after HI to a separate group with hemispheric volume loss (P10, Nissl) and sex determined.</p> Results <p>IN BRT_002 resulted in lower plasma and brain exposure (lower C<sub>max</sub> and AUC<sub>tot</sub>) with minimal levels at 24&#xa0;h compared to IP administration in Sham and HI animals. Brain BRT_001 exposure increased slightly with limited effects on elimination kinetics after HI. Plasma PK did not show effects by sex, but sex affected select brain/injury determinations. IN BRT_002 did not reduce HI hemispheric volume loss.</p> Conclusion <p>IN BRT_002 administration produced limited brain exposure to BRT_001 and did not provide neuroprotection after HI. These findings emphasize the importance of PK-guided validation for brain exposures, targets, and neuroprotection when drugs are given by the IN route.</p>

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Pharmacokinetics and Brain Distribution of a Purine-Derived Neuroprotective Agent after Intranasal Administration in Neonatal Rats with Hypoxic–Ischemic Brain Injury

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • Auriane Maïza,
  • Clemence Disdier,
  • Amalia Tsintzou,
  • Anvi Laetitia Nguyen,
  • Alain Pruvost,
  • Frederic Théodoro,
  • Zexi Zang,
  • Bingqing Wang,
  • Nassima Oumata,
  • Hervé Galons,
  • Barbara S. Stonestreet,
  • Aloïse Mabondzo,
  • Xiaodi F. Chen

摘要

Purpose

Hypoxic–ischemic (HI) brain injury results in death and lifelong disabilities in newborns. Pharmaceutical agents are not available to treat HI brain injury. We reported that intraperitoneal (IP) BRT_002 is neuroprotective after HI in neonatal rodents. We examined whether intranasal (IN) BRT_002 provides adequate exposure by measuring plasma/brain PK, brain distribution, brain-to-plasma ratios, and hemispheric volume loss after HI, and compared results to our published findings after IP administration.

Methods

Metabolic stability of BRT_002 and its metabolite BRT_001 was examined in rat and human liver microsomes. Postnatal day P7 sham or HI-exposed rats given IN BRT_002 (30 mg/kg) had plasma and ipsilateral brain BRT_002/BRT_001 quantified by LC–MS/MS at 1, 2, 6, and 24 h along with PK parameters (Cmax, AUCtot, t1/2) and brain-to-plasma ratios derived. IN BRT_002 was given at 0, 24, and 48 h after HI to a separate group with hemispheric volume loss (P10, Nissl) and sex determined.

Results

IN BRT_002 resulted in lower plasma and brain exposure (lower Cmax and AUCtot) with minimal levels at 24 h compared to IP administration in Sham and HI animals. Brain BRT_001 exposure increased slightly with limited effects on elimination kinetics after HI. Plasma PK did not show effects by sex, but sex affected select brain/injury determinations. IN BRT_002 did not reduce HI hemispheric volume loss.

Conclusion

IN BRT_002 administration produced limited brain exposure to BRT_001 and did not provide neuroprotection after HI. These findings emphasize the importance of PK-guided validation for brain exposures, targets, and neuroprotection when drugs are given by the IN route.