Evaluation of Systemic and Brain Pharmacokinetic Parameters for Repurposing Metformin Using Intravenous Bolus Administration

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2024, Volume and Issue: 392(1), P. 100013 - 100013

Published: May 22, 2024

Metformin's potential in treating ischemic stroke and neurodegenerative conditions is of growing interest. Yet, the absence established systemic brain pharmacokinetic (PK) parameters at relevant preclinical doses presents a significant knowledge gap. This study highlights these PK importance using pharmacologically to pharmacodynamics related diseases. A liquid chromatography with tandem mass spectrometry method measure metformin levels plasma, brain, cerebrospinal fluid was developed validated. In vitro assays examined tissue binding metabolic stability. Intravenous bolus administration C57BL6 mice covered low- high-dose range maintaining pharmacological relevance. Quantification used assess parameters, such as unidirectional blood-to-brain constant (Kin) unbound brain-to-plasma ratio (Kp, uu, brain). Metformin exhibited no mouse plasma remained metabolically stable. It rapidly entered reaching detectable little 5 minutes. Kin value 1.87 ± 0.27 μL/g/min obtained. As dose increased, Kp, showed decreased value, implying saturation, but this did not affect an increase absolute concentrations. quantifiable 30 minutes over time, concentrations lower than those across all doses. Our findings emphasize selection based on for studies. We anticipate further investigations focusing PKs disease conditions, stroke. SIGNIFICANCE STATEMENT: The establishes crucial diseases, addressing emphasizes selecting highlight metformin's rapid entry, minimal binding, necessity considering studies provides foundation future into efficacy disease(s).

Language: Английский

Imidazole Bioisostere Activators of Endopeptidase Neurolysin with Enhanced Potency and Metabolic Stability

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(4), P. 510 - 517

Published: March 29, 2024

The peptidase neurolysin (Nln) has been validated as a potential target for developing therapeutics ischemic stroke (IS). Overexpression of Nln in mouse model IS provides significant cerebroprotection, leading to reduced infarction size and edema volume. Pharmacological inhibition the post-stroke brain worsens neurological outcomes. A virtual screen identified dipeptide small-molecule activators Nln. Optimization studies resulted class peptidomimetic compounds with promising activity. However, these still possessed an amide bond that compromised their stability plasma brain. Herein, we report synthesis characterization series bioisosteres based on our leads. Imidazole-based afford scaffolds increased potency activate combined enhanced significantly better permeability over original hits.

Language: Английский

Systemic and Brain Pharmacokinetics of Milnacipran in Mice: Comparison of Intraperitoneal and Intravenous Administration

Pharmaceutics, Journal Year: 2023, Volume and Issue: 16(1), P. 53 - 53

Published: Dec. 29, 2023

Milnacipran is a dual serotonin and norepinephrine reuptake inhibitor, clinically used for the treatment of major depression or fibromyalgia. Currently, there are no studies reporting pharmacokinetics (PK) milnacipran after intraperitoneal (IP) injection, despite this being primary administration route in numerous experimental using drug. Therefore, present study was designed to investigate PK profile IP-administered mice compare it intravenous (IV) route. First liquid chromatography–mass spectrometry (LC-MS/MS) method developed validated accurately quantify biological samples. The blood brain samples collected at various time-points post-administration. Non-compartmental analyses were employed determine key parameters. maximum concentration (Cmax) drug plasma 5 min IP administration, whereas brain, 60 both routes administration. Curiously, majority parameters similar irrespective route, bioavailability 92.5% injection. These findings provide insight into milnacipran’s absorption, distribution, elimination characteristics first time should be valuable future pharmacological studies.

Language: Английский