Sharma Sejal, Zhang Yong, Patel Dhavalkumar, Akter Khondker Ayesha, Bagchi Sounak, Sifat Ali Ehsan, Nozohouri Ehsan, Ahn Yeseul, Karamyan Vardan T, Bickel Ulrich, Abbruscato Thomas J
Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas; Center for Blood-Brain Barrier Research and Brain Drug Discovery, Texas Tech University Health Sciences Center, Amarillo, Texas.
Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas; Center for Blood-Brain Barrier Research and Brain Drug Discovery, Texas Tech University Health Sciences Center, Amarillo, Texas; Office of Sciences, Jerry. H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas.
J Pharmacol Exp Ther. 2025 Jan;392(1):100013. doi: 10.1124/jpet.124.002152. Epub 2024 Nov 22.
Metformin's potential in treating ischemic stroke and neurodegenerative conditions is of growing interest. Yet, the absence of established systemic and brain pharmacokinetic (PK) parameters at relevant preclinical doses presents a significant knowledge gap. This study highlights these PK parameters and the importance of using pharmacologically relevant preclinical doses to study pharmacodynamics in stroke and related neurodegenerative diseases. A liquid chromatography with tandem mass spectrometry method to measure metformin levels in plasma, brain, and cerebrospinal fluid was developed and validated. In vitro assays examined brain tissue binding and metabolic stability. Intravenous bolus administration of metformin to C57BL6 mice covered a low- to high-dose range maintaining pharmacological relevance. Quantification of metformin in the brain was used to assess brain PK parameters, such as unidirectional blood-to-brain constant (K) and unbound brain-to-plasma ratio (K). Metformin exhibited no binding in the mouse plasma and brain and remained metabolically stable. It rapidly entered the brain, reaching detectable levels in as little as 5 minutes. A K value of 1.87 ± 0.27 μL/g/min was obtained. As the dose increased, K showed decreased value, implying saturation, but this did not affect an increase in absolute brain concentrations. Metformin was quantifiable in the cerebrospinal fluid at 30 minutes but decreased over time, with concentrations lower than those in the brain across all doses. Our findings emphasize the importance of metformin dose selection based on PK parameters for preclinical pharmacological studies. We anticipate further investigations focusing on PKs and pharmacodynamics in disease conditions, such as stroke. SIGNIFICANCE STATEMENT: The study establishes crucial pharmacokinetic parameters of metformin for treating ischemic stroke and neurodegenerative diseases, addressing a significant knowledge gap. It further emphasizes the importance of selecting pharmacologically relevant preclinical doses. The findings highlight metformin's rapid brain entry, minimal binding, and metabolic stability. The necessity of considering pharmacokinetic parameters in preclinical studies provides a foundation for future investigations into metformin's efficacy for neurodegenerative disease(s).
二甲双胍在治疗缺血性中风和神经退行性疾病方面的潜力越来越受到关注。然而，在相关临床前剂量下缺乏既定的全身和脑药代动力学（PK）参数，这存在重大的知识空白。本研究突出了这些PK参数以及使用药理学相关的临床前剂量来研究中风和相关神经退行性疾病药效学的重要性。开发并验证了一种采用液相色谱 - 串联质谱法测量血浆、脑和脑脊液中二甲双胍水平的方法。体外试验检测了脑组织结合和代谢稳定性。对C57BL6小鼠静脉推注二甲双胍，涵盖了低至高剂量范围，保持了药理学相关性。脑内二甲双胍的定量用于评估脑PK参数，如单向血脑常数（K）和非结合脑血比（K）。二甲双胍在小鼠血浆和脑中无结合，且代谢稳定。它迅速进入脑内，在短短5分钟内即可达到可检测水平。获得的K值为1.87±0.27μL/g/min。随着剂量增加，K值降低，意味着出现饱和，但这并不影响脑内绝对浓度的增加。在30分钟时脑脊液中可检测到二甲双胍，但随着时间推移而降低，所有剂量下其浓度均低于脑内浓度。我们的研究结果强调了基于PK参数选择二甲双胍剂量用于临床前药理学研究的重要性。我们预计未来将进一步研究疾病状态（如中风）下的PK和药效学。意义声明：该研究建立了二甲双胍治疗缺血性中风和神经退行性疾病的关键药代动力学参数，填补了重大的知识空白。它进一步强调了选择药理学相关临床前剂量的重要性。研究结果突出了二甲双胍快速进入脑内、结合极少和代谢稳定的特点。在临床前研究中考虑药代动力学参数的必要性为未来研究二甲双胍对神经退行性疾病的疗效奠定了基础。
