Pharmacokinetics of Intraperitoneally Delivered Glucagon in Pigs: A Hypothesis of First Pass Metabolism

Teigen, Ingrid Anna; Åm, Marte Kierulf; Carlsen, Sven Magnus; Christiansen, Sverre Christian

doi:10.1007/s13318-021-00692-2

Cited by 6 publications

(11 citation statements)

References 35 publications

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“…Arterial blood samples were drawn immediately before each glucagon bolus, and subsequently every 2 min for the first 40 min, every 5 min for the next 60 min, and every 10 min for the remaining 50 min. We set the observation time to 150 min to ensure a wash‐out period of more than five estimated T 1/2 between each bolus 12,15 …”

Section: Methodsmentioning

confidence: 99%

“…We set the observation time to 150 min to ensure a wash-out period of more than five estimated T 1/2 between each bolus. 12,15…”

Section: Blood Samplingmentioning

confidence: 99%

“…8 In contrast, the pharmacological properties of IP delivered glucagon have only been studied in a few small-sized animal trials. [9][10][11][12][13] To our knowledge, no comparative pharmacokinetic studies of intravenously (IV), SC, and IP delivered glucagon have been published. Thus, we investigated possible differences in glucagon pharmacokinetics based on the route of administration using a pig model.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, we investigated possible differences in glucagon pharmacokinetics based on the route of administration using a pig model. The primary aim of this study was to investigate the bioavailability of glucagon after IP administration, potentially providing evidence for our previously published hypothesis of extensive first‐pass metabolism of glucagon in the liver 12 . Other relevant pharmacokinetic parameters, such as maximum plasma concentration (C max ), time to C max (T max ), time to last measurable concentration (T last ), plasma elimination half‐life (T 1/2 ) and area under time‐plasma concentration curve from time zero to T last (AUC 0‐last ), after IV, IP and SC glucagon administration were evaluated as secondary outcomes.…”

Section: Introductionmentioning

confidence: 99%

“…Unihormonal pumps administering solely insulin IP have demonstrated superiority over SC pumps in reducing glycated haemoglobin (HbA1c) and hypoglycaemic/hyperglycaemic episodes in humans 8 . In contrast, the pharmacological properties of IP delivered glucagon have only been studied in a few small‐sized animal trials 9–13 …”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of glucagon after intravenous, intraperitoneal and subcutaneous administration in a pig model

Teigen

Åm

Carlsen

et al. 2022

Basic Clin Pharma Tox

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Introduction There is increasing scientific evidence to substantiate using low‐dose glucagon as a supplement to insulin therapy in artificial pancreata for diabetes mellitus type 1. The delivery of both these hormones intraperitoneally would mimic normal physiology. However, our knowledge of the pharmacological properties of glucagon after intraperitoneal administration is limited. This study compared the pharmacokinetics of glucagon after intraperitoneal, subcutaneous and intravenous administration and the pharmacodynamic effects of glucagon on glucose metabolism after intraperitoneal and subcutaneous administration in a pig model. Materials and methods Twelve pigs were included. Glucagon was administered intraperitoneally, subcutaneously and intravenously in a randomised order. Arterial samples were collected every 2–10 min for 150 min to determine plasma glucagon and blood glucose concentrations. Results The bioavailability of glucagon was significantly lower after intraperitoneal compared with subcutaneous administration with a median difference (95% confidence interval) of 13% (4–22). The effect of glucagon on glucose metabolism was equal after intraperitoneal and subcutaneous administration. Conclusions Intraperitoneal glucagon administration resulted in lower systemic glucagon exposure than subcutaneous administration without loss of efficiency. We interpret this as evidence of a major first‐pass metabolism of glucagon in the liver.

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Section: Methodsmentioning

confidence: 99%

“…We set the observation time to 150 min to ensure a wash-out period of more than five estimated T 1/2 between each bolus. 12,15…”

Section: Blood Samplingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Pharmacokinetics of glucagon after intravenous, intraperitoneal and subcutaneous administration in a pig model

Teigen

Åm

Carlsen

et al. 2022

Basic Clin Pharma Tox

Self Cite

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Pharmacokinetics of cyproheptadine hydrochloride in mice and beagle dogs, tissue distribution, and excretion properties of cyproheptadine hydrochloride in mice

Liu,

Cui,

Zhou

2024

Separation Science Plus

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Cyproheptadine hydrochloride (CYP) is a typical antihistamine with antiserotonergic, blocking H1 receptor, anticholine, anti‐inflammatory and anti‐allergic effects. To investigate the pharmacokinetics, biodistribution, and excretion, the liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method was established and validated the CYP concentrations in the plasma of beagle dogs and the biological matrix of mice. CYP was quickly absorbed into the bloodstream and widely distributed to various tissues. The area under the curve (AUC)0–t and peak concentration of CYP were increased with the dose after administration. At the equal dose, the bioavailability of intramuscular injection in mice and beagle dogs was 81.1% and 79.1%. The tissue distribution experiments suggested that CYP would not accumulate for a long time in vivo. CYP levels in tissues peaked after 15 min of injection, and the drug concentrations in the kidney and lung were higher than those in other tissues. For excretion, the cumulative urinary excretion of CYP within 156 h after intramuscular injection in mice accounted for (1.2 ± 0.1)% of the total administration dose. The feces excretion of the drug prototype was below the lower limit of quantitation. High sensitivity and strong specificity are observed based on the established method of LC‐MS/MS, which was successfully applied to the pharmacokinetics, tissue distribution, and excretion studies of CYP.

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The artificial pancreas: two alternative approaches to achieve a fully closed-loop system with optimal glucose control

Åm,

Teigen,

Riaz

et al. 2023

J Endocrinol Invest

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Introduction Diabetes mellitus type 1 is a chronic disease that implies mandatory external insulin delivery. The patients must monitor their blood glucose levels and administer appropriate insulin boluses to keep their blood glucose within the desired range. It requires a lot of time and endeavour, and many patients struggle with suboptimal glucose control despite all their efforts. Materials and methods This narrative review combines existing knowledge with new discoveries from animal experiments. Discussion In the last decade, artificial pancreas (AP) devices have been developed to improve glucose control and relieve patients of the constant burden of managing their disease. However, a feasible and fully automated AP is yet to be developed. The main challenges preventing the development of a true, subcutaneous (SC) AP system are the slow dynamics of SC glucose sensing and particularly the delay in effect on glucose levels after SC insulin infusions. We have previously published studies on using the intraperitoneal space for an AP; however, we further propose a novel and potentially disruptive way to utilize the vasodilative properties of glucagon in SC AP systems. Conclusion This narrative review presents two lesser-explored viable solutions for AP systems and discusses the potential for improvement toward a fully automated system: A) using the intraperitoneal approach for more rapid insulin absorption, and B) besides using glucagon to treat and prevent hypoglycemia, also administering micro-boluses of glucagon to increase the local SC blood flow, thereby accelerating SC insulin absorption and SC glucose sensor site dynamics.

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Pharmacokinetics of Intraperitoneally Delivered Glucagon in Pigs: A Hypothesis of First Pass Metabolism

Cited by 6 publications

References 35 publications

Pharmacokinetics of glucagon after intravenous, intraperitoneal and subcutaneous administration in a pig model

Pharmacokinetics of glucagon after intravenous, intraperitoneal and subcutaneous administration in a pig model

Pharmacokinetics of cyproheptadine hydrochloride in mice and beagle dogs, tissue distribution, and excretion properties of cyproheptadine hydrochloride in mice

The artificial pancreas: two alternative approaches to achieve a fully closed-loop system with optimal glucose control

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