DOI: 10.5061/dryad.fbg79cp5q
title: 7,8-Dihydroxyflavone pharmacokinetic data in neonatal mice with Hypoxia-Ischemia related brain injury

description: Introduction: 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. Methods: 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. Results:
 Our PK analyses show that plasma 7,8-DHF concentrations followed a
 two-compartment PK model, with more than 95% eliminated by 3 hours 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&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. Conclusion: 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.
description: 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. Plasma
 and brain samples were collected at 10 min, 30 min, 1 hr, and 3 hr
 post-7,8-DHF injection. A liquid chromatography-tandem mass spectrometry
 method was developed to quantitate the drug and two O-methylated
 metabolite concentration in plasma samples, as well as in samples from the
 left and right brain hemispheres. 
description: # 7,8-Dihydroxyflavone pharmacokinetic data in neonatal mice with
 Hypoxia-Ischemia related brain injury
 [https://doi.org/10.5061/dryad.fbg79cp5q](https://doi.org/10.5061/dryad.fbg79cp5q) ## Description of the data and file structure ### Files and variables #### File: 7\_8\_DHF\_Plasma\_and\_Brain\_PK\_in\_Neonatal\_Mice\_with\_HI\_Brain\_Injury\_Raw\_Data.xlsx **Description:** PK data at various time points ##### Variables and units * Surgery_type: sham vs. surgically induced hypoxic-ischemic brain injury * Sex: male vs. female * Dose: 5 mg/kg only * Nominal Time: planned time of sample collection, minute * Actual Time: actual time of sample collection, minute * Br_R_Concentration: right brain hemisphere concentration, ng/g * Br_L_Concentration: left brain hemisphere concentration, ng/g * Plasma_Concentration: plasma concentration, ng/mL * Plasma_M147_Conc: 7H8M-flavone plasma concentration, ng/mL * Plasma_M162_Conc: 8H7M-flavone plasma concentration, ng/mL * Left_br_M147_Conc: left brain hemisphere concentration of 7H8M-flavone, ng/g * Left_br_M162_Conc: left brain hemisphere concentration of 8H7M-flavone, ng/g * Right_br_M147_Conc: right brain hemisphere concentration of 7H8M-flavone, ng/g * Right_br_M162_Conc: right brain hemisphere concentration of 8H7M-flavone, ng/g **Data codes** * n/a: data not available, samples used for method development * BQL: below quantification limit