Pharmacokinetics of Lixisenatide, a GLP-1 Receptor Agonist, Determined by a Novel Liquid Chromatography–Tandem Mass Spectrometry Analysis in Rats

Abstract

Because of its greater binding affinity and longer half-life than native glucagon-like peptide-1 (GLP-1), the GLP-1 receptor agonist lixisenatide is commonly used to treat type 2 diabetes mellitus. This study aimed to establish a simple and robust liquid chromatography–tandem mass spectrometry (LC–MS/MS) approach for lixisenatide for in vivo pharmacokinetic investigation. Methanol-based protein precipitation with formic acid was exploited for plasma sample extraction, using esomeprazole as the internal standard. Gradient elution with 0.1% formic acid in distilled water and acetonitrile was utilized for chromatographic separation. Mass spectrometry was used to monitor the MRM transition at m/z 810.8 → 129.2 for lixisenatide. In rat plasma, lixisenatide had a lower limit of quantification of 10 ng/mL. The LC–MS/MS was applied to describe the pharmacokinetics of lixisenatide in rats following intravenous and subcutaneous dosing. The average half-life of lixisenatide was 0.37 ± 0.06 h after intravenous injection. The estimated subcutaneous bioavailability of lixisenatide was 2.17%. This LC–MS/MS analysis might be relevant in future research to create novel dosage formulations of lixisenatide and other GLP-1 receptor agonists with optimal therapeutic effectiveness.