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.