Zheng Qiang, He Shuai, Xu Song-Lin, Ma Meng-Die, Fan Min, Ge Jin-Fang
School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, PR China.
Anhui Provincial Laboratory of Inflammatory and Immune Disease, Anhui Institute of Innovative Drugs, Hefei, Anhui 230032, PR China.
Saudi Pharm J. 2024 Feb;32(2):101934. doi: 10.1016/j.jsps.2023.101934. Epub 2023 Dec 23.
To investigate the pharmacokinetics and tissue distribution of VGB racemate and its single enantiomers, and explore the potential of clinic development for single enantiomer S-VGB.
In the pharmacokinetics study, male Sprague-Dawley rats were gavaged with VGB racemate or its single enantiomers dosing 50, 100 or 200 mg/kg, and the blood samples were collected during 12 h at regular intervals. In the experiment of tissue distribution, VGB and its single enantiomers were administered intravenously dosing 200 mg/kg, and the tissues including heart, liver, spleen, lung and kidney, eyes, hippocampus, and prefrontal cortex were separated at different times. The concentrations of R-VGB and S-VGB in the plasma and tissues were measured using HPLC.
Both S-VGB and R-VGB could be detected in the plasma of rats administered with VGB racemate, reaching Cmax at approximately 0.5 h with t 2-3 h. There was no significant pharmacokinetic difference between the two enantiomers when VGB racemate was given 200 mg/kg and 100 mg/kg. However, when given at the dose of 50 mg/kg, S-VGB presented a shorter t and a higher Cl/F than R-VGB, indicating a faster metabolism of S-VGB. Furthermore, when single enantiomer was administered respectively, S-VGB presented a slower metabolism than R-VGB, as indicated by a longer t and MRT but a lower Cmax. Moreover, compared with the VGB racemate, the single enantiomers S-VGB and R-VGB had shorter t and MRT, higher Cmax and AUC/D, and lower Vz/F and Cl/F, indicating the stronger oral absorption and faster metabolism of single enantiomer. In addition, regardless of VGB racemate administration or single enantiomer administration, S-VGB and R-VGB had similar characteristics in tissue distribution, and the content of S-VGB in hippocampus, prefrontal cortex and liver was much higher than that of R-VGB.
Although there is no transformation between S-VGB and R-VGB in vivo, those two enantiomers display certain disparities in the pharmacokinetics and tissue distribution, and interact with each other. These findings might be a possible interpretation for the pharmacological and toxic effects of VGB and a potential direction for the development and optimization of the single enantiomer S-VGB.
研究VGB消旋体及其单一对映体的药代动力学和组织分布，并探讨单一对映体S-VGB的临床开发潜力。
在药代动力学研究中，将雄性Sprague-Dawley大鼠分别灌胃给予50、100或200mg/kg的VGB消旋体或其单一对映体，并在12小时内定期采集血样。在组织分布实验中，静脉注射给予200mg/kg的VGB及其单一对映体，并在不同时间分离心脏、肝脏、脾脏、肺、肾、眼睛、海马体和前额叶皮质等组织。采用高效液相色谱法测定血浆和组织中R-VGB和S-VGB的浓度。
给予VGB消旋体的大鼠血浆中均可检测到S-VGB和R-VGB，给药后约0.5小时达到Cmax，t为2-3小时。给予200mg/kg和100mg/kg的VGB消旋体时，两种对映体的药代动力学无显著差异。然而，给予50mg/kg剂量时，S-VGB的t较短，Cl/F较高，表明S-VGB的代谢更快。此外，分别给予单一对映体时，S-VGB的代谢比R-VGB慢，表现为t和MRT较长，但Cmax较低。而且，与VGB消旋体相比，单一对映体S-VGB和R-VGB的t和MRT较短，Cmax和AUC/D较高，Vz/F和Cl/F较低，表明单一对映体的口服吸收更强，代谢更快。另外，无论给予VGB消旋体还是单一对映体，S-VGB和R-VGB在组织分布上具有相似的特征，海马体、前额叶皮质和肝脏中S-VGB的含量远高于R-VGB。
虽然S-VGB和R-VGB在体内不存在相互转化，但这两种对映体在药代动力学和组织分布上存在一定差异，并相互影响。这些发现可能是对VGB药理和毒理作用的一种可能解释，也是单一对映体S-VGB开发和优化的潜在方向。
