Assessment of the potential drug-drug interaction between carvedilol and clopidogrel mediated through intestinal P-glycoprotein.

The most widely prescribed oral antiplatelet agent, clopidogrel, shows high interindividual variability resulting in an increased risk of cardiovascular events in the patients with reduced platelet inhibition. The purpose of this study was to investigate the role of the P-glycoprotein (P-gp) efflux pump in limiting the intestinal permeability of clopidogrel and the effect of a ß-blocker, namely, carvedilol, on its intestinal transport. Effective permeabilities (Peff) of clopidogrel and carvedilol were investigated in the proximal jejunum and distal ileum of rats using an in situ intestinal perfusion model. Peff values of clopidogrel and carvedilol were found to be concentration dependent with decreased Peff values at the low perfusate concentrations. Coperfusion with the P-gp inhibitors verapamil (100 µM) and carvedilol (10 µM) significantly increased the Peff of clopidogrel in the jejunum (8.31±0.20 x 10-5 and 6.98±0.75 x 10-5 vs. 3.60±0.51 x 10-5, respectively) and ileum (9.08±2.19 x 10-5 and 8.35±1.58 x 10-5 vs. 3.85±0.15 x 10-5, respectively). However, at the highest concentration tested (30 µM), clopidogrel exhibited 3 and 1.4 times higher Peff than those of metoprolol, an FDA high permeability reference standard, in the jejunum and ileum, respectively. Overall, this study indicates that the efflux function appears not to have a significant impact on the in vivo intestinal absorption of clopidogrel due to the saturation of P-gp, suggesting no clinically relevant interaction between carvedilol and clopidogrel mediated through P-gp at intestinal level.

A lecithin-based microemulsion of rh-insulin with aprotinin for oral administration: Investigation of hypoglycemic effects in non-diabetic and STZ-induced diabetic rats.

The aim of this study was to develop a microemulsion formulation providing an improved efficacy of orally administered insulin. The microemulsions were prepared using Labrafil M 1944 CS, Phospholipon 90 G (lecithin), absolute alcohol and bi-distilled water. The microemulsions of recombinant human (rh)-insulin and aqueous solution (200 IU/kg) were administered intragastrically by a canulla to diabetic and non-diabetic rats. Aprotinin (2500 KIU/g) was added as the enzyme inhibitor to the formulation. Upon the administration of intragastric rh-insulin solution (IS) to non-diabetic rats, the plasma glucose and insulin levels were not changed significantly. Therefore, the hypoglycemic effect caused by subcutaneous rh-insulin solution (SC), microemulsion containing rh-insulin (IME) and microemulsion containing rh-insulin and aprotinin (IMEA) were analyzed in diabetic rats. The area above the plasma glucose levels time curves (AAC), minimum glucose concentration (Cmin) and time to Cmin (tmin) were derived from the plasma glucose profiles. IME and IMEA caused approximately 30% decrease in plasma glucose levels. The decrease in the plasma glucose levels continued after the 90th min. The highest AAC value was obtained when IMEA was administered to rats. The maximum plasma insulin concentration (Cmax), time to reach Cmax (tmax), terminal half-life (t(1/2)), area under the plasma concentration-time curve (AUC), mean residence time (MRT) and elimination rate constant (k(el)) values were also calculated. It was observed that t(1/2) values varied between 0.53 and 1.31h. No significant difference could be found between the pharmacokinetic parameters of the IME and IMEA administered groups. Addition of aprotinin to the microemulsion containing rh-insulin increased bioavailability when compared to those not containing it, although the difference is not significant.

Rheological, mucoadhesive and release properties of pluronic F-127 gel and pluronic F-127/polycarbophil mixed gel systems.

This study was designed to combine the mucoadhesive property of Noveon and the thermosensitive property of Pluronic F-127 into one gel system. A rheological study of Pluronic aqueous sols (10-35%), Noveon gels (0.5-2%) and of mixed gels containing Pluronic (10-17.5%) and polycarbophil (0.5-2.5%) was conducted at different temperatures (15-35 degrees C). The viscosity of Pluronic sols increased with an increase in temperature and the mixed gels had thermoreversible property. The viscosity of mixed gels was higher than that of the Pluronic sols containing only Pluronic because of the increase in total polymer concentration. No interaction was found between -COOH groups of Noveon and Pluronic molecules at the studied concentrations of polymers; the viscosity of mixed gels containing un-neutralized Noveon was lower than that of the neutralized mixed gels. The effect of Pluronic F-127 on the mucoadhesive property of Noveon was investigated. The mucoadhesive properties of Pluronic and Noveon gels were compared by a force of detachment test. It was found that Pluronic and Noveon gels showed approximately the same mucoadhesive strength. However, there were significant differences in the viscosity of Noveon and Pluronic gels. The adhesive force of the mixed gel was almost same as that of the Noveon gel. The Pluronic did not affect the adhesive power of Noveon and the increased viscosity did not affect the bioadhesive force of the mixed gels. In spite of increasing viscosity of the gel, the percentage of released model material (mannitol) increased with increasing temperature. This is based on the previously reported observation that the interaction between the Pluronic molecules squeezed mannitol molecules out of the polymer chains. The mannitol release obeyed zero-order kinetics and the flux values of mixed gels at 15 and 35 degrees C were very similar. The Noveon chains among Pluronic chains probably hindered the diffusion of mannitol molecules and the release was thus controlled by Noveon. The combination of a thermosensitive polymer like Pluronic and a bioadhesive polymer like Noveon appears promising from a pharmaceutical viewpoint. These gel systems may find use in the development of bioadhesive, thermosensitive and controlled release formulations.