Lim Sin Yin, Scarlett Cameron O, Yapici Sefer, Ferrazzano Peter, Cengiz Pelin
Pharmacy Practice and Translational Research Division, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, United States.
Analytical Instrumentation Center, School of Pharmacy, University of Wisconsin-Madison, Madison, WI, United States.
Front Pharmacol. 2025 Jan 15;15:1508696. doi: 10.3389/fphar.2024.1508696. eCollection 2024.
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.
Left-sided HI brain injury was induced in postnatal day 9 (P9) mice, followed by a 5 mg/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.
Our PK analyses show that plasma 7,8-DHF concentrations followed a two-compartment PK model, with more than 95% eliminated by 3 h 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 < 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.
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.
7,8 - 二羟基黄酮（7,8 - DHF）在多种脑损伤模型中是一种有前景的转化治疗药物，包括小鼠新生儿缺氧缺血（HI）模型。然而，仅在患有HI脑损伤的雌性新生小鼠中观察到7,8 - DHF的神经保护作用，而在雄性小鼠中未观察到。尚不清楚HI诱导的生理变化是否会使雄性和雌性小鼠对7,8 - DHF的脑内分布产生不同影响。我们旨在评估性别对实验性诱导HI脑损伤后新生小鼠血浆和脑内7,8 - DHF药代动力学的影响。
在出生后第9天（P9）的小鼠中诱导左侧HI脑损伤，随后腹腔注射5 mg/kg的7,8 - DHF。开发了一种液相色谱 - 串联质谱法来定量血浆样品以及左右脑半球样品中的药物浓度。使用非线性混合效应模型分析血浆和脑内浓度 - 时间数据。采用半定量方法评估血浆和脑样品中7,8 - DHF的两种活性O - 甲基化代谢产物（8H7M - 黄酮和7H8M - 黄酮）的浓度。
我们的药代动力学分析表明，血浆中7,8 - DHF浓度遵循二室药代动力学模型，腹腔注射后3小时内超过95%的药物被清除。性别与7,8 - DHF的药代动力学无显著相关性；然而，HI脑损伤与清除率降低21%相关（p < 0.01）。7,8 - DHF向脑内的分布迅速；然而，脑内分布程度较低，右脑和左脑与血浆的分配系数分别为8.6%和9.9%。此外，在血浆和脑内均检测到7,8 - DHF的两种O - 甲基化代谢产物。
新生小鼠中7,8 - DHF的血浆和脑内药代动力学在雄性和雌性之间相似。在未来评估7,8 - DHF治疗效果的研究中，应考虑7,8 - DHF脑内分布程度较低以及活性代谢产物的潜在影响。
