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

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.