Date Published: April 4, 2019
Publisher: Public Library of Science
Author(s): Armin Mooranian, Nassim Zamani, Ryu Takechi, Giuseppe Luna, Momir Mikov, Svetlana Goločorbin-Kon, Magdy Elnashar, Frank Arfuso, Hani Al-Salami, Clemens Fürnsinn.
Type 2 diabetes (T2D) is characterised by β-cell damage and hyperglycaemia. The lipophilic drug, probucol, has shown significant β-cell protective and potential antidiabetic effects, which were enhanced by hydrophilic bile acid incorporation using taurocholic acid and chenodeoxycholic acid. However, probucol has severe cardiotoxicity and a variable absorption profile, which limit its potential applications in T2D. Accordingly, this study aimed to design multiple formulations to optimise probucol oral delivery in T2D and test their effects on probucol absorption and accumulation in the heart. Adult male mice were given a high fat diet (HFD), and a week later, injected with a single dose of alloxan to accelerate T2D development, and once diabetes confirmed, divided into three groups (six to seven mice each). The groups were gavaged a daily dose of probucol powder, probucol microcapsules, or probucol-bile acid microcapsules for three months, and euthanized; and blood, tissues, and feces collected for blood glucose and probucol concentration analyses. Probucol concentrations in plasma were similar among all the groups. Groups given probucol microcapsules and probucol-bile acid microcapsules showed significant reduction in probucol accumulation in the heart compared with the group given probucol powder (p<0.05). Probucol microencapsulation with or without bile acids reduced its accumulation in heart tissues, without changing plasma concentrations, which may be beneficial in reducing its cardiotoxicity and optimise its potential applications in T2D.
Type-2 Diabetes (T2D) arises from interactions between the genetic background and environmental triggers. The genetic background has been studied but with limited major discoveries due to the complexity of the human genome and its association with environmental triggers such as obesity. Genome-wide association studies provide useful information on the correlation between nucleotide polymorphism with the incidence of T2D using a large sample size . These studies can provide information on genetic predisposition to the development and progression of T2D . Damage of pancreatic β-cells exhibit a certain genetic signature that is part of the process of T2D development and progression. In a study by Kirkpatrick C et al; authors showed that there is a negative correlation between genes encoding the potassium channel in β-cells and the patients’ body mass index . In another study by Wali J et al; the authors reviewed the role of β-cell apoptosis in the development and progression of T2D and concluded that cell damage occurs in two main ways, cellular stress (intrinsic) or activation of apoptotic inducing receptors (extrinsic) . Environmental factors include inactivity and lipid disturbances. Accordingly, T2D therapy needs to target not only hyperglycaemia but also β-cell inflammation and damage, and lipid disturbances.
Sodium alginate (SA, 99%), probucol (PB, 98%, C31H48O2S2) and alloxan were all purchased from Sigma-Aldrich (St. Louis, USA). Water soluble gel was supplied by Scharlab S.L. Australia. NM30D (Eudragit polymer) was acquired from Evonik (Vic, Australia). The rodent diets were supplied by Specialty Feeds (Perth, Australia). The water used to dissolve the reagents was HPLC quality purchased from Merck Australia (Sydney, Australia).
Despite probucol possessing anti-atherosclerotic and weight controlling effects , the mice weights remained similar regardless of probucol treatment or formulation used (Table 1). The lack of effects of probucol treatment on mice weight suggests that any potential antidiabetic effects of probucol are likely to be anti-inflammatory or hypoglycaemic (Fig 3).
Probucol was initially marketed in the 1970s as a new anti-atherosclerotic drug to treat hypercholesterolemia. Probucol showed significant lipid regulatory effects, but at high concentrations, was associated with prolonged QT intervals and cardiotoxic side effects. Brown KF, et al; investigated methods to predicting change in QT interval induced by probucol administration. The authors found that there was prolongation of the QT interval, which was directly associated with increased plasma concentrations following probucol uptake, and these findings linked probucol oral absorption kinetics with its cardiotoxic side effects . Studies in our laboratory have shown optimisation of probucol delivery via microencapsulation technology [6–8, 10, 11]. However, to the best of our knowledge, probucol encapsulation in NM30D-ursodeoxychonlic acid, and investigation of its hypoglycaemic, anti-inflammatory, absorption, and cardiac accumulation profiles in T2D mice, has not been explored. This study complements ongoing work on probucol applications in cardiometabolic disorders .
Overall, the findings demonstrate potential effects of our microencapsulated probucol in glycaemic control and T2D therapy. Microencapsulated probucol had similar absorption and systemic concentration profiles, but enhanced pharmacological activity. Further studies are needed to ascertain the clinical efficacy of the microcapsules in the management of diabetes mellitus.