Abstract
Background/Aim: Gliclazide is one of the most commonly prescribed oral anti-hyperglycaemic therapies in type 2 diabetes mellitus (T2D). Recently reported additional beneficial pharmacological properties of gliclazide, including immunomodulatory and anticoagulant activities, suggested its potential application in treatment of type 1 diabetes mellitus (T1D). However, following oral administration, gliclazide was shown to have poor and variable absorption directing research into development of novel pharmaceutical delivery systems of gliclazide suitable for T1D. Since bile acids have previously demonstrated stabilising and controlled-release effects on microcapsules, their use for preparation of microcapsules of gliclazide may lead to improvements in gliclazide release, absorption and antidiabetic effects. This investigation was aimed to evaluate drug absorption profiles and hypoglycaemic effects of alginate-based microcapsules of gliclazide, prepared together with or without cholic acid, in healthy rats. Methods: Thirty healthy Wistar rats with confirmed normal glucose blood concentration were allocated into five groups and administered with a single dose of either vehicle microcapsules, gliclazide in suspension, gliclazide microcapsules, gliclazide in suspension together with cholic acid or microencapsulated gliclazide in combination with cholic acid. Following respective gliclazide dose, blood was sampled over next 10 hours and blood glucose levels and gliclazide serum concentrations were measured. Results: This analysis demonstrated altered effects of different gliclazide formulations in healthy rats with the highest gliclazide absorption mirrored by the most profound hypoglycaemic effect being achieved after its oral administration as a suspension (p <0.01) compared to any other investigated pharmaceutical formulation. Concusion: When conducting pharmacokinetic characterisation of novel pharmaceutical formulations of antidiabetic drugs, it is of utmost importance to select the appropriate research model and consider the possible role of gut-metabolic activation on their hypoglycaemic effects.
Highlights
Gliclazide, a second-generation sulphonylurea, is the second most commonly prescribed oral antihyperglycemic agent in the treatment of type 2 diabetes mellitus (T2D), after metformin.[1]
All administered gliclazide formulations, with or without added cholic acid resulted in significantly lower blood glucose concentrations in healthy rats compared with control vehicle microcapsules, indicating a strong and significant hypoglycaemic effects of orally administered gliclazide (Figure 1)
Addition of cholic acid to gliclazide microcapsules resulted in significantly higher concentrations in serum compared to non-microencapsulated combination of gliclazide and respective bile acid (p < 0.05)
Summary
Gliclazide, a second-generation sulphonylurea, is the second most commonly prescribed oral antihyperglycemic agent in the treatment of type 2 diabetes mellitus (T2D), after metformin.[1]. Jovic et al Scr Med 2020;51(1):[15,16,17,18,19,20], phonylurea receptor (SUR1) and subsequent stimulation of insulin release, as well as for its unique antioxidant properties[2] and other beneficial haematological effects.[3, 4] gliclazide was shown to restore peripheral insulin sensitivity, decrease hepatic glucose production and skeletal muscle glycogenesis, independent of its insulin-mediated effects.[5] Due to its known extrapancreatic action, gliclazide may exert conceivable potential in type 1 diabetes mellitus (T1D) treatment, especially when used in combination with other agents that exhibit hypoglycaemic effects, including certain bile acids and probiotics, as previously reported.[6,7,8]
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