Pharmacokinetics of 4-Hydroxybenzaldehyde in Normal and Cerebral Ischemia–Reperfusion Injury Rats Based on Microdialysis Technique,European Journal of Drug Metabolism and Pharmacokinetics

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Pharmacokinetics of 4-Hydroxybenzaldehyde in Normal and Cerebral Ischemia–Reperfusion Injury Rats Based on Microdialysis Technique
European Journal of Drug Metabolism and Pharmacokinetics ( IF 1.9 ) Pub Date : 2023-11-24 , DOI: 10.1007/s13318-023-00863-3
Chunping Xu ₁ , Jin Feng ₁ , Hang Sun ₁ , Mingli Yan ₁ , Qian Yang ₁ , Xiaonan Zhou ₁ , Jianguang Yang ₁ , Fangyan He _{1,

2} , Qing Lin _{1,

2}

Affiliation

Aim

4-Hydroxybenzaldehyde (4-HBd) is used for the treatment of headaches, dizziness, and convulsions. The objective of this study was to characterize the pharmacokinetics of 4-HBd in cerebral ischemia-reperfusion injury (CIRI) rats by microdialysis technology with high-performance liquid chromatography with diode-array detection (HPLC-DAD) and ultra-performance liquid chromatography–mass spectrometry (UPLC-MS).

Methods

Microdialysis was used to collect blood, feces, and urine of normal and CIRI model rats. Pharmacokinetic parameters were determined using HPLC-DAD and 4-HBd metabolites were determined using UPLC-MS.

Results

After gavage of 4-HBd in normal and middle cerebral artery occlusion/reperfusion (MCAO/R) rats, it was widely distributed to all tissues (heart, liver, spleen, lung, kidney, and brain) in both the equilibrium and elimination phases, and the distribution pattern was basically the same; the highest concentration was found in the brain. The absolute bioavailability of 4-HBd was 5.33%; however, after intragastric administration in normal and MCAO/R rats, fecal and urinary excretion of 4-HBd accounted for 0.02% and 0.01% and for 0.01% and 0.03% of the dosage, respectively. Furthermore, 4-HBd was rapidly metabolized into 4-hydroxybenzoic acid (4-HBA) after administration in both the control and MCAO/R groups. Compared with the control, the peak time of 4-HBd plasma concentration in the MCAO/R rats decreased from 10.67 min to 8.83 min, the area under the concentration-time curve decreased significantly, and the half-life increased from 31.81 min to 78.85 min.

Conclusions

The rapid absorption and low absolute bioavailability of 4-HBd by gavage in rats are followed by rapid and wide distribution to various tissues and organs, including the brain. The prototype drug is excreted in the feces and urine in low amounts, and it is metabolized to 4-HBA in large amounts in vivo; the pathological state of the MCAO/R model mainly affects its absorption degree and metabolism rate.

中文翻译：

基于微透析技术的4-羟基苯甲醛在正常和脑缺血再灌注损伤大鼠中的药代动力学

目的

4-羟基苯甲醛 (4-HBd) 用于治疗头痛、头晕和惊厥。本研究的目的是通过微透析技术、二极管阵列检测高效液相色谱 (HPLC-DAD) 和超高效液相色谱来表征 4-HBd 在脑缺血再灌注损伤 (CIRI) 大鼠中的药代动力学。质谱（UPLC-MS）。

方法

采用微透析收集正常大鼠和CIRI模型大鼠的血液、粪便和尿液。使用 HPLC-DAD 测定药代动力学参数，使用 UPLC-MS 测定 4-HBd 代谢物。

结果

正常和大脑中动脉闭塞/再灌注 (MCAO/R) 大鼠灌胃 4-HBd 后，在平衡期和消除期均广泛分布到所有组织（心、肝、脾、肺、肾和脑），分布格局基本一致；在大脑中发现浓度最高。 4-HBd的绝对生物利用度为5.33%；然而，正常大鼠和MCAO/R大鼠灌胃后，粪便和尿液中4-HBd的排泄量分别占给药剂量的0.02%和0.01%和0.01%和0.03%。此外，对照组和 MCAO/R 组给药后，4-HBd 迅速代谢为 4-羟基苯甲酸 (4-HBA)。与对照组相比，MCAO/R大鼠4-HBd血药浓度达峰时间由10.67 min缩短至8.83 min，浓度-时间曲线下面积显着减小，半衰期由31.81 min延长至78.85 min。分钟。