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. 2023 Apr 15:1221:123688.
doi: 10.1016/j.jchromb.2023.123688. Epub 2023 Mar 22.

Novel LC-MS/MS analysis of the GLP-1 analog semaglutide with its application to pharmacokinetics and brain distribution studies in rats

Tae Suk Lee  1 , Eun Ji Park  2 , Minkyu Choi  1 , Hyun Seok Oh  1 , Yejin An  3 , Taehyung Kim  1 , Tae Hwan Kim  4 , Beom Soo Shin  5 , Soyoung Shin  6
Affiliations

Novel LC-MS/MS analysis of the GLP-1 analog semaglutide with its application to pharmacokinetics and brain distribution studies in rats

Tae Suk Lee et al. J Chromatogr B Analyt Technol Biomed Life Sci. .

Abstract

Semaglutide, one of the most potent glucagon-like peptide (GLP)-1 analogs, has widely been used to treat type II diabetes mellitus and obesity. Recent studies have shown that semaglutide also works on the brain, suggesting its potential utility for various diseases, including Parkinson's disease and Alzheimer's disease. This study aimed to develop a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of semaglutide in both plasma and brain to characterize the pharmacokinetics and brain distribution in rats. Semaglutide was extracted by simple protein precipitation with methanol from plasma and by solid phase extraction from brain tissue. Liraglutide was used as an internal standard. Gradient elution profiles with mobile phases comprising 0.1 % formic acid in water and acetonitrile were used for chromatographic separation. The lower limit of quantification (LLOQ) of the LC-MS/MS assay was 0.5 ng/mL for both rat plasma and brain. Intra- and inter-day accuracy ranged 89.20-109.50 % in the plasma and 92.00-105.00 % in the brain. Precision was within 8.92 % in the plasma and 7.94 % in the brain. Sprague-Dawley rats were given semaglutide by intravenous (IV, 0.02 mg/kg) and subcutaneous (SC, 0.1 and 0.2 mg/kg) injection. Plasma concentrations of semaglutide showed a multi-exponential decline with an average half-life of 7.22-9.26 hr in rats. The subcutaneous bioavailability of semaglutide was 76.65-82.85 %. The brain tissue to plasma partition coefficient (Kp) value of semaglutide was estimated as <0.01. Among the different regions of the brain, semaglutide concentrations were significantly higher in the hypothalamus. The analytical method and pharmacokinetic information may be helpful toward a better understanding of the effect of semaglutide in the brain and further development of GLP-1 analogs for various brain diseases.

Keywords: Bioavailability; Brain distribution; GLP-1 analogs; Hypothalamus; LC-MS/MS; Pharmacokinetics; Semaglutide.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Beom Soo Shin reports financial support was provided by Korea Ministry of Trade Industry and Energy. Eun Ji Park reports a relationship with D&D Pharmatech that includes: employment.].

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