Simultaneous quantitative determination of liraglutide and insulin degludec in rat plasma by liquid chromatography–tandem mass spectrometry method and its application

Zhai, Jianping; Li, Li; Dong, Lei; Dong, Kelly; Xiang, Song; Gui, Luolan; Zhang, Jiaying; Song, Haifeng; Ge, Zhiqiang

doi:10.1002/bmc.4921

Cited by 9 publications

(7 citation statements)

References 16 publications

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“…The t 1/2 generated by TCA-RA method was within 5.40–6.43 h, which is longer than that of Degludec as reported to be 2.9 h and 2.3 h in rats. 34 , 35 The results also indicated that INS061 should possess a longer in vivo duration compared to Degludec, which is a strong evidence for its long-acting effects. In addition, the long-acting efficacy of INS601 on glucose lowering in STZ-induced diabetic rats further supported its prolonged duration in vivo.…”

Section: Discussionmentioning

confidence: 84%

“…Whether INS061 is superior to Degludec, in terms of efficacy and the duration of action in the human body, requires future clinical investigation. However, according to the comparison of PK behaviors of Degludec in rats and humans reported in the literatures, 34,35,41 we are confident that INS061 is a potential effective and long-acting insulin analogue.…”

Section: Discussionmentioning

confidence: 85%

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Efficacy, Pharmacokinetics, Biodistribution and Excretion of a Novel Acylated Long-Acting Insulin Analogue INS061 in Rats

Pan

Shi

et al. 2021

DDDT

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Purpose Long-acting insulin analogues are known to be a major player in the management of glucose levels in type I diabetic patients. However, highly frequent hypo- and hyperglycemic incidences of current long-acting insulins are the important factor to limit stable management of glucose level for clinical benefits. To further optimize the properties for steadily controlling glucose level, a novel long-acting insulin INS061 was designed and its efficacy, pharmacokinetics, biodistribution and excretion profiles were investigated in rats. Methods The glucose-lowering effects were evaluated in a streptozocin-induced diabetic rats compared to commercial insulins via subcutaneous administration. The pharmacokinetics, biodistribution, and excretion were examined by validated analytical methods including radioactivity assay and radioactivity assay after the precipitation with TCA and the separation by HPLC. Results INS061 exhibited favorable blood glucose lowering effects up to 24 h compared to Degludec. Pharmacokinetic study revealed that the concentration-time curves of INS061 between two administration routes were remarkably different. Following intravenous administration, INS061 was quickly distributed to various organs and tissues and slowly eliminated over time with urinary excretion being the major route for elimination, and the maximum plasma concentrations (Cmax) and systemic exposures (AUC) increased in a linear manner. Conclusion The present structural modifications of human insulin possessed a long-acting profile and glucose-lowering function along with favorable in vivo properties in rats, which establish a foundation for further preclinical and clinical evaluation.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 85%

Efficacy, Pharmacokinetics, Biodistribution and Excretion of a Novel Acylated Long-Acting Insulin Analogue INS061 in Rats

Pan

Shi

et al. 2021

DDDT

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“…Extraction recovery was evaluated using six replicates of LQC, MQC, and HQC concentration levels. It was determined by comparing the peak area of the analytes in plasma spiked samples before and after extraction (Zhai et al, 2020; Zhu et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

Simultaneous quantitative determination of insulin aspart and insulin degludec in human plasma using simple shoot LC method

Abdelwaly

Mohamed

El-Kosasy

et al. 2021

Biomedical Chromatography

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Combining short-acting and long-acting insulin analogs was a real challenge that was overcome by NovoNordisk through the co-formulation of insulin aspart and insulin degludec in single-dosage form. The proposed study provides a simple, short, and reliable HPLC method with diode array detection that is developed and validated for the simultaneous determination of insulin aspart and insulin degludec in human plasma. The proposed method achieved good separation between the two analytes utilizing a C8 column at 35 C in a very short run time (6 min), with a simple, low-cost, and reliable extraction method through precipitation of plasma protein. Gradient elution was applied using a mobile phase consisting of 0.1 M sodium sulfate (pH 3.4) and acetonitrile. The method was validated according to EMA Guideline on Bioanalytical Validation. The proposed method had a linear range from 3.0 to 300 μg/mL for insulin aspart and from 3.5 to 300 μg/mL for insulin degludec. The intra-and inter-day precision of insulin aspart were 0.36-3.33% and 1.59-8.84%, respectively, and accuracy was between 10.06 and 3.09% The intra-and inter-day precision of insulin degludec were 0.29-1.93% and 0.89-5.14%, respectively, and accuracy was between À5.29 and 3.91%.

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“…As the molecular weight of liraglutide is large (m.w. = 3751.2), multiply charged precursor ions are often selected for MRM analysis (Dong et al 2018;Meng et al 2017;Sauter et al 2019;Zhai et al 2020). In the present study, the most abundant precursor ion in the positive Q1 mass scan spectrum was [M + 4H] 4+ at m/z 938.5 for liraglutide and [M + 4H] 4+ at m/z 1029.4 for IS (semaglutide).…”

Section: Lc-ms/ms Conditionsmentioning

confidence: 99%

“…Recent advances in LC-MS/MS have been overcoming its limitations of poor ionization, significant endogenous interference, and low sensitivity in the bioanalysis of peptides and proteins (Dong et al 2018;Meng et al 2017;Pinho et al 2019;Ewles and Goodwin 2011). There are several LC-MS/MS methods available for the determination of liraglutide in the plasma (Dong et al 2018;Meng et al 2017;Sauter et al 2019;Zhai et al 2020). However, no LC-MS/MS methods have been reported to determine liraglutide concentrations in the tissues.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and brain distribution of the therapeutic peptide liraglutide by a novel LC–MS/MS analysis

Choi

Lee

et al. 2023

J Anal Sci Technol

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Liraglutide is a glucagon-like peptide-1 (GLP-1) analog that has been utilized for the treatment of type 2 diabetes mellitus. Liraglutide at a higher dose also shows beneficial effects in weight loss, which prompted its widespread use as an anti-obesity drug. The potential of liraglutide to treat Alzheimer’s disease and cognitive impairment has also been suggested. Nevertheless, the pharmacokinetics of liraglutide, including its distribution to the brain, has not been fully characterized. Therefore, this study aimed to develop a simple and sensitive bioanalytical method using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and determine the pharmacokinetics and brain distribution of liraglutide in rats. Liraglutide in the rat plasma and brain tissue homogenates was extracted by protein precipitation using methanol. A gradient elution profile was used for chromatographic separation with mobile phases comprising 0.3% formic acid in water and 0.3% formic acid in acetonitrile. The mass spectrometry was operated in the positive electrospray ionization with multiple reaction monitoring mode. The lower limit of quantification of the present LC–MS/MS was 1 ng/mL in the plasma and 2 ng/mL in the brain tissue. Following intravenous injection (0.05 mg/kg, n = 5), plasma concentrations of liraglutide decreased monoexponentially with an average half-life of 3.67 h. The estimated absolute bioavailability of liraglutide after subcutaneous injection was 13.16%. Brain distribution of liraglutide was not significant, with the tissue-to-plasma partition coefficient (Kp) of liraglutide less than 0.00031. However, the concentrations of liraglutide were significantly different in the different brain regions following IV injection. In the brain, liraglutide concentrations were the highest in the hypothalamus, followed by the cerebellum and cerebrum. The present LC–MS/MS assay and the pharmacokinetic results may be helpful to understand better the effect of liraglutide in the brain for further preclinical and clinical studies of liraglutide.

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Simultaneous quantitative determination of liraglutide and insulin degludec in rat plasma by liquid chromatography–tandem mass spectrometry method and its application

Cited by 9 publications

References 16 publications

Efficacy, Pharmacokinetics, Biodistribution and Excretion of a Novel Acylated Long-Acting Insulin Analogue INS061 in Rats

Efficacy, Pharmacokinetics, Biodistribution and Excretion of a Novel Acylated Long-Acting Insulin Analogue INS061 in Rats

Simultaneous quantitative determination of insulin aspart and insulin degludec in human plasma using simple shoot LC method

Pharmacokinetics and brain distribution of the therapeutic peptide liraglutide by a novel LC–MS/MS analysis

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