Permeability Of Atenolol Research Articles

Formulation and Evaluation of Atenolol Nanocrystals Using 3(2) Full Factorial Design

Background: Atenolol is a commonly used antihypertensive drug of class III BCS category. It suffers from the problem of poor intestinal absorption or permeability thus low bioavailability. The objective of the present study was to enhance the permeability of atenolol by using a suitable technique, which is economical and devoid of using any organic solvent. Methods: The nanocrystal technology by high-pressure homogenization was chosen for this purpose, which is a less expensive and simple method. In this technique, no organic solvent was used. The study was further aimed to characterize prepared nanocrystals in the solid state by Fourier Transform Infrared Spectroscopy (FTIR), Powder X-Ray Diffraction (PXRD) patterns, particle size, zeta potential, %yield and drug permeation study through isolated goat’s intestine. An in-vivo study was carried out to determine the pharmacokinetic property in comparison to pure drug powder using rats as experimental animals. The formulation design was optimized by a 3(2) factorial design. In these designs, two factors namely surfactant amount (X1) and speed of homogenizer (X2) were evaluated on three dependent variables namely particle size (y1), zeta potential (y2) and production yield (y3). Results: PXRD study indicated the presence of high crystal content in the prepared formulation. These nanocrystal formulations were found with a narrow size range from 125 nm to 652 nm and positive zeta potential of 16-18 mV. Optimized formulations showed almost 90% production yield. Permeability study revealed 90.88% drug release for optimized formulation in comparison to the pure drug (31.22%). The FTIR study also exposed that there was no disturbance in the principal peaks of the pure drug atenolol. This confirmed the integrity of the pure drug and its compatibility with the excipients used. A significant increase in the area under the concentration-time curve Cpmax and MRT for nanocrystals was observed in comparison to the pure drug. The higher values of the determination coefficient (R2) of all three parameters indicated the goodness of fit of the 3(2) factorial model. The factorial analysis also revealed that speed of homogenizer had a bigger effect on particle size (-0.2812), zeta potential (-0.0004) and production yield (0.0192) whereas amount of surfactant had a lesser effect on production yield (-370.4401), zeta potential (-43.3651) as well as particle size (-6169.2601). Conclusion: It is concluded that the selected method of nanocrystal formation and its further optimization by factorial design was effective to increase the solubility, as well as permeability of atenolol. Further, the systematic approach of factorial design provides rational evaluation and prediction of nanocrystals formulation on the selected limited number of smart experimentation.

Effect of Common Excipients on Intestinal Drug Absorption in Wistar Rats.

The aim of the present paper is to study the effect of common excipients on the permeability of atenolol (as drug absorbed mainly by passive diffusion) and rhodamine (as P-glycoprotein substrate). The apparent permeability was measured by an in situ perfusion method in Wistar rats using the closed loop Doluisio's method. Permeability values were characterized in the absence and presence of 18 commonly used excipients. Excipient concentrations were selected based on the amounts in oral immediate release dosage forms, which failed the test during the human bioequivalence studies. Atenolol was studied with and without excipients in the whole small intestine, whereas rhodamine was tested in three different intestinal segments to account for the differential expression of P-glycoprotein, and it was further on tested in the ileum, in the presence of excipients. Atenolol presented higher permeability values when it was administered with colloidal silica, croscarmellose, hydroxypropyl methylcellulose (HPMC), magnesium stearate, MgCO3, poly(ethylene glycol) 400, poly(vinylpyrrolidone), sorbitol, starch, and TiO2 rhodamine showed higher permeability values when it was administered with croscarmellose and HPMC. On the one hand, the mechanisms of action were not discernible with the proposed experiments. On the other hand, commercial formulations do not present a single excipient but several, which can counteract their effects. The in situ perfusion technique can be useful for a preliminary screening and risk analysis, while the in vivo pharmacokinetic results would be needed to define conclusive effects.

Atenolol Renal Secretion Is Mediated by Human Organic Cation Transporter 2 and Multidrug and Toxin Extrusion Proteins.

Atenolol is a β-blocker widely used in the treatment of hypertension. Atenolol is cleared predominantly by the kidney by both glomerular filtration and active secretion, but the molecular mechanisms involved in its renal secretion are unclear. Using a panel of human embryonic kidney cell lines stably expressing human organic cation transporter (hOCT) 1-3, human organic anion transporter (hOAT) 1, hOAT3, human multidrug and toxin extrusion protein (hMATE) 1, and hMATE2-K, we found that atenolol interacted with both organic cation and anion transporters. However, it is transported by hOCT1, hOCT2, hMATE1, and hMATE2-K, but not by hOCT3, hOAT1, and hOAT3. A detailed kinetic analysis coupled with absolute quantification of membrane transporter proteins by liquid chromatography-tandem mass spectrometry revealed that atenolol is an excellent substrate for the renal transporters hOCT2, hMATE1, and hMATE2-K. The Km values for hOCT2, hMATE1, and hMATE2-K are 280 ± 4, 32 ± 5, and 76 ± 14 μM, respectively, and the calculated turnover numbers are 2.76, 0.41, and 2.20 s(-1), respectively. To demonstrate unidirectional transepithelial transport of atenolol, we developed and functionally validated a hOCT2/hMATE1 double-transfected Madin-Darby canine kidney cell culture model. Transwell studies showed that atenolol transport in the basal (B)-to-apical (A) direction is 27-fold higher than in the A-to-B direction, whereas its B-to-A/A-to-B transport ratio was only 2 in the vector-transfected control cells. The overall permeability of atenolol in the B-to-A direction in hOCT2/hMATE1 cells was 44-fold higher than in control cells. Together, our data support that atenolol tubular secretion is mediated through the hOCT2/hMATEs secretion pathway and suggest a significant role of organic cation transporters in the disposition of an important antihypertensive drug.

Differential effect of oxidative stress on intestinal apparent permeability of drugs transported by paracellular and transcellular route

Increased intestinal permeability of macromolecules is a common feature of oxidative stress-induced gastrointestinal diseases; how it affects the absorption of drugs is not investigated. Hence, it was proposed to study the influence of hydrogen peroxide-induced oxidative stress on permeability of atenolol and metoprolol using a modified everted rat intestine technique. Atenolol was chosen as a marker of paracellular drug transport and metoprolol was selected to represent transcellular drug transport. Wistar rats were used as a source of intestine, which was everted using a glass rod, mounted on permeability apparatus, having test drug (100 μg/ml in Krebs) in donor compartment. Samples were taken from receiver compartment every 5 min for 60 min, and analyzed by HPLC. For induction of oxidative stress isolated ileum was incubated in H₂O₂ (200 μM) containing Krebs for 15 min and then again permeability was estimated. Extent of oxidative stress was determined by estimating lipid peroxidation using thiobarbituric acid assay, which was found to be increased by 42 % in hydrogen peroxide treated rat intestine as compared to control group. The mean apparent permeability of atenolol and metoprolol was found to be 0.054 ± 0.024 × 10⁻⁴ and 0.84 ± 0.14 × 10⁻⁴ cm/s, respectively, in control group rat intestinal segments. After exposure to hydrogen peroxide, there was a significant increase in the mean permeability of atenolol (0.11 ± 0.01 × 10⁻⁴ cm/s), however, metoprolol permeability was unaltered (0.94 ± 0.047 × 10⁻⁴ cm/s). The marked increase in the apparent permeability of atenolol may be attributed to rupture of intestinal barrier. In conclusion, the present study reports the differential effect of oxidative stress-induced damage on drug transport across rat intestine.

In Vitro Drug Permeation Enhancement Potential of Aloe Gel Materials

Aloe vera gel previously showed the ability to increase the bioavailability of vitamins and to enhance the in vitro transport of a macromolecular drug across intestinal epithelial cell monolayers. The purpose of this study is to investigate the potential of other species of aloe to act as drug absorption enhancement agents. The effect of gel materials from three South African aloes; Aloe ferox, A. marlothii and A. speciosa on the transepithelial electrical resistance and permeability of atenolol across excised intestinal tissue of the rat as well as the transport of FITC-dextran across Caco-2 cell monolayers was investigated. The aloe gel materials exhibited the ability to statistically significantly reduce the transepithelial electrical resistance of excised rat intestinal tissue but did not significantly increase the transport of atenolol across this in vitro tissue model at the concentrations tested. At least one concentration of each aloe gel material enhanced the transport of FITC-dextran statistically significantly across Caco-2 cell monolayers. The aloe gel materials showed potential to act as drug absorption enhancing agents across intestinal epithelia. The absorption enhancement effect was dependent on the type of in vitro model and type of drug was investigated.

Permeability of atenolol and propranolol in the presence of dimethyl sulfoxide in rat single‐pass intestinal perfusion assay with liquid chromatography/UV detection

A simple and sensitive RP-HPLC-UV method was developed and validated for simultaneous determination of atenolol and propranolol and subsequently applied to investigate the effect of dimethyl sulfoxide in rat in situ intestinal permeability studies. Atenolol (400 microm) and propranolol (100 microm) were perfused in the small intestine of anaesthetized (pentobarbitone sodium 60 mg/kg, i.p.) male Sprague-Dawley rats either in the presence (1, 3 and 5%) or in the absence of dimethyl sulfoxide. There was no significant alteration (p > 0.05) in the permeability of atenolol and propranolol, which indicated there was no effect of various concentrations of dimethyl sulfoxide (1-5%) on the membrane integrity of the rat intestinal tissues. The analytical method was validated on a C(4) column with a mobile phase comprising ammonium acetate buffer (pH 3.5, 0.02 m) and acetonitrile in the ratio of 30:70 (v/v) at a flow rate of 1.0 mL/min. The validated method was found to be accurate and precise and stability studies were carried out at different storage conditions and both analytes were found to be stable. These findings are applicable for determining the absorbability of water-insoluble drugs and new chemical entities for the purpose of classifying them in the biopharmaceutical classification system.