Bioavailability and hypoglycemic activity of the semisynthetic bile acid salt, sodium 3α,7α-dihydroxy-12-0X0-5β-cholanate, in healthy and diabetic rats

Mikov, Momir; Boni, N. S.; Al‐Salami, Hani; Kuhajda, Ksenija; Kevrešan, Slavko; Goločorbin-Kon, Svetlana; Fawcett, J. Paul

doi:10.1007/bf03190984

Cited by 30 publications

(10 citation statements)

References 14 publications

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“…In fact, in diabetic rats, a hyperglycemic effect was observed over the first three hours post-dose. However, MKC produced a modest hypoglycemic effect when given alone, as shown in previous studies (35). The combination of gliclazide and MKC produced a hypoglycemic effect which was signficantly greater in diabetic rats, and it was independent of insulin production.…”

Section: Discussionmentioning

confidence: 78%

The influence of 3α,7α-dihydroxy-12-keto-5β-cholanate on gliclazide pharmacokinetics and glucose levels in a rat model of diabetes

Mikov

Al‐Salami

Goločorbin-Kon

et al. 2008

Eur. J. Drug Metabol. Pharmacokinet.

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The aim of this study was to investigate the pharmacokinetics and glucose-lowering activity of gliclazide alone and in combination with the bile acid salt, sodium 3alpha,7alpha-dihydroxy-12-keto-5beta-cholanate (MKC), in a rat model of type I diabetes. Eighty male Wistar rats were divided into eight groups (n=10). Four groups were treated with alloxan (30 mg/kg) to induce diabetes. One group of healthy and one group of diabetic rats were administered gliclazide (20 mg/kg), MKC (4 mg/kg) or a combination of gliclazide (20 mg/kg) and MKC (4 mg/kg). One group of healthy and one group of diabetic rats were used as controls. Blood samples were collected from the tail vein 6 hours post-dose and the plasma was analyzed for glucose concentrations. It was found that gliclazide bioavailability was increased in healthy rats when coadministered with MKC, but there was no difference in glucose levels. Gliclazide bioavailability was much lower in diabetic rats and was not altered by MKC. However, the hypoglycemic effect of the combination of gliclazide and MKC was significantly greater in diabetic rats than that of gliclazide alone. It was demonstrated that the combination of MKC and gliclazide produced a significant hypoglycemic effect in a rat model of Type I diabetes. As gliclazide alone does not have a hypoglycemic effect on Type I diabetic rats, it can be concluded that gliclazide potentiates hypoglycemic effect of MKC in Type I diabetic rats.

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Section: Discussionmentioning

confidence: 78%

The influence of 3α,7α-dihydroxy-12-keto-5β-cholanate on gliclazide pharmacokinetics and glucose levels in a rat model of diabetes

Mikov

Al‐Salami

Goločorbin-Kon

et al. 2008

Eur. J. Drug Metabol. Pharmacokinet.

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“…Diabetes was induced by injecting alloxan 30 mg/kg intravenously into the tail vein (16,28). Rats were considered diabetic if blood glucose concentration was >20 mmol/l and serum insulin <0.04 Ilg/l, 2-3 days after injection.…”

Section: Animal Protocolmentioning

confidence: 99%

Gliclazide reduces MKC intestinal transport in healthy but not diabetic rats

Al‐Salami

Butt

Tucker

et al. 2009

Eur. J. Drug Metabol. Pharmacokinet.

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The aim is to investigate the influence of the antidiabetic drug gliclazide on the ileal permeation of the semisynthetic bile acid, MKC, in tissues from healthy and diabetic rats. Sixteen Wistar rats (350 +/- 50 g) were randomly allocated into four groups (4 rats per group, 8 chambers per rat, i.e., n=32) two of which were made diabetic (given alloxan i.v. 30 mg/kg). Group 1 was used to measure the permeation of MKC (50 microg/ml) alone (control) while group 2 to measure MKC permeation in the presence of gliclazide (200 microg/ml). The diabetic groups 3 (gliclazide) and 4 (MKC+gliclazide) were treated in the same way. Rats were sacrificed and tissues were mounted into the Ussing chamber for the measurement of MKC mucosal to serosal (absorptive) and serosal to mucosal (secretory) fluxes. In healthy tissues, gliclazide reduced MKC absorptive flux (p < 0.01) and increased its secretory flux (p < 0.01). In diabetic tissues, gliclazide had no effect on either the absorptive or the secretory fluxes of MKC. The lack of effect of gliclazide on MKC permeation in diabetic tissues suggests the absence or suppressed drug transporters. Furthermore, gliclazide inhibition of MKC absorptive flux and induction of MKC secretory flux in healthy tissues may result from the selective inhibition of an efflux drug transporter.

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“…Analysis of crystal depositions on the microcapsule surfaces ( Figure 5 ) revealed high levels of Na and Cl ions, confirming that there were small crystals of NaCl on the surface of G-DCA-SA microcapsules; this was expected, given sodium chloride is a by-product of the ionic-gelation methodology of microcapsule production. 16 , 19 , 20 Both formulations showed high levels of sulfur, oxygen, and carbon, confirming the presence of G within the polymer matrix for the formulation, although carbon and oxygen are also common to DCA and SA. As for the microcapsule surface composition, EDXR revealed high levels of calcium, carbon, and oxygen, which were expected, given the microcapsule wall structure and DCA-reinforced calcium alginate matrix system.…”

Section: Resultsmentioning

confidence: 71%

Novel artificial cell microencapsulation of a complex gliclazide-deoxycholic bile acid formulation: a characterization study

Mooranian¹,

Negrulj²,

Chen-Tan³

et al. 2014

DDDT

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Gliclazide (G) is an antidiabetic drug commonly used in type 2 diabetes. It has extrapancreatic hypoglycemic effects, which makes it a good candidate in type 1 diabetes (T1D). In previous studies, we have shown that a gliclazide-bile acid mixture exerted a hypoglycemic effect in a rat model of T1D. We have also shown that a gliclazide-deoxycholic acid (G-DCA) mixture resulted in better G permeation in vivo, but did not produce a hypoglycemic effect. In this study, we aimed to develop a novel microencapsulated formulation of G-DCA with uniform structure, which has the potential to enhance G pharmacokinetic and pharmacodynamic effects in our rat model of T1D. We also aimed to examine the effect that DCA will have when formulated with our new G microcapsules, in terms of morphology, structure, and excipients’ compatibility. Microencapsulation was carried out using the Büchi-based microencapsulating system developed in our laboratory. Using sodium alginate (SA) polymer, both formulations were prepared: G-SA (control) at a ratio of 1:30, and G-DCA-SA (test) at a ratio of 1:3:30. Complete characterization of microcapsules was carried out. The new G-DCA-SA formulation was further optimized by the addition of DCA, exhibiting pseudoplastic-thixotropic rheological characteristics. The size of microcapsules remained similar after DCA addition, and these microcapsules showed no chemical interactions between the excipients. This was supported further by the spectral and microscopy studies, suggesting microcapsule stability. The new microencapsulated formulation has good structural properties and may be useful for the oral delivery of G in T1D.

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Bioavailability and hypoglycemic activity of the semisynthetic bile acid salt, sodium 3α,7α-dihydroxy-12-0X0-5β-cholanate, in healthy and diabetic rats

Cited by 30 publications

References 14 publications

The influence of 3α,7α-dihydroxy-12-keto-5β-cholanate on gliclazide pharmacokinetics and glucose levels in a rat model of diabetes

The influence of 3α,7α-dihydroxy-12-keto-5β-cholanate on gliclazide pharmacokinetics and glucose levels in a rat model of diabetes

Gliclazide reduces MKC intestinal transport in healthy but not diabetic rats

Novel artificial cell microencapsulation of a complex gliclazide-deoxycholic bile acid formulation: a characterization study

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