In vitro metabolic stability of exendin-4: pharmacokinetics and identification of cleavage products.

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Liao S, Liang Y, Zhang Z, Li J, Wang J, Wang X, Dou G, Zhang Z, Liu K

In vitro metabolic stability of exendin-4: pharmacokinetics and identification of cleavage products.

PLoS One. 2015 Feb 27;10(2):e0116805. doi: 10.1371/journal.pone.0116805. eCollection 2015.

PubMed ID

25723538 [ View in PubMed

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Abstract

The aim of this study was to investigate the metabolic stability and cleavage sites of exendin-4 in rat tissue homogenates, as well as to identify the types of proteases involved in exendin-4 degradation. The stability of exendin-4 in kidney and liver homogenates from rats was evaluated using liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) with gradient elution. Furthermore, we used a combination of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and LC-ESI-MS/MS to identify the structures of the major degradation products of exendin-4, and peptidase inhibitors were used to characterize exendin-4 degradation in rat liver and kidney homogenates and to identify the proteases involved in exendin-4 metabolism. Exendin-4 had a half-life of 7.8 and 100.9 min in the kidney and liver homogenate, respectively. The enzymes most likely to be involved in the degradation of exendin-4 were aminopeptidases, serineproteases, and metalloproteases. Exendin-4(15-39) and exendin-4(16-39) were the predominant direct exendin-4 metabolites in the kidney, and the main product of exendin-4 metabolism in the liver was exendin-4(12-39). Our results indicated that the metabolism of exendin-4 involved an initial endoproteolytic cleavage and subsequent exoproteolytic digestion. The degradation of exendin-4 in the kidney and liver homogenates followed distinct patterns, and the primary cleavage sites of exendin-4 degradation in rat kidney homogenates were located after AA-14, and -15, whereas those in rat liver homogenates were located after AA-11.

DrugBank Data that Cites this Article

Drugs

Exenatide

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Exenatide	Dipeptidyl peptidase 4	Protein	Humans	Unknown	Substrate	Details