{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:35:47Z","timestamp":1785411347587,"version":"3.56.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T00:00:00Z","timestamp":1736899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>7,8-Dihydroxyflavone (7,8-DHF) is a promising translational therapy in several brain injury models, including the neonatal hypoxia-ischemia (HI) model in mice. However, the neuroprotective effect of 7,8-DHF was only observed in female, but not male, neonatal mice with HI brain injury. It is unknown whether HI-induced physiological changes affect brain distribution of 7,8-DHF differently for male versus female mice. We aimed to evaluate the impact of sex on the pharmacokinetics of 7,8-DHF in plasma and brain neonatal mice following experimentally induced HI brain injury.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Left-sided HI brain injury was induced in postnatal day 9 (P9) mice, followed by a 5\u00a0mg\/kg intraperitoneal injection of 7,8-DHF. A liquid chromatography-tandem mass spectrometry method was developed to quantitate the drug concentration in plasma samples, as well as in samples from the left and right brain hemispheres. A nonlinear mixed-effects model was used to analyze the plasma and brain concentration-time data. A semi-quantitative approach was used to evaluate the concentrations of two active O-methylated metabolites of 7,8-DHF (8H7M-flavone and 7H8M-flavone) in both plasma and brain samples.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our PK analyses show that plasma 7,8-DHF concentrations followed a two-compartment PK model, with more than 95% eliminated by 3\u00a0h after the IP injection. Sex was not significantly associated with the PK of 7,8-DHF; however, HI brain injury was associated with a 21% reduction in clearance (p &amp;lt; 0.01). The distribution of 7,8-DHF to the brain was rapid; however, the extent of brain distribution was low with the right and left brain-to-plasma partition coefficients being 8.6% and 9.9%, respectively. Additionally, both O-methylated metabolites of 7,8-DHF were detected in the plasma and brain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The plasma and brain PK of 7,8-DHF in neonatal mice were similar between males and females. The low extent of 7,8-DHF brain distribution and the potential effects of the active metabolites should be considered in future studies evaluating the therapeutic effects of 7,8-DHF.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1508696","type":"journal-article","created":{"date-parts":[[2025,1,15]],"date-time":"2025-01-15T12:54:01Z","timestamp":1736945641000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Pharmacokinetics of 7,8-dihydroxyflavone in neonatal mice with hypoxia-ischemia related brain injury"],"prefix":"10.3389","volume":"15","author":[{"given":"Sin Yin","family":"Lim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron O.","family":"Scarlett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sefer","family":"Yapici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Ferrazzano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pelin","family":"Cengiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/0887-8994(94)90009-4","article-title":"Cerebral blood flow in preterm infants affected by sex, mechanical ventilation, and intrauterine growth","volume":"11","author":"Baenziger","year":"1994","journal-title":"Pediatr. 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