Digoxin absorption decreased independently of P-gp activity in rats with irinotecan-induced gastrointestinal damage

Background Irinotecan (CPT-11) is clinically known to cause severe diarrhea and gastrointestinal damage. Recently, we have reported that CPT-11-induced gastrointestinal damage is associated with the upregulation of intestinal P-glycoprotein (P-gp) expression and decreased absorption of its substrate, dabigatran etexilate (DABE), using a rat model. However, the P-gp activity or its contribution to the decreased absorption remains unclear. The aim of this study was to quantitatively evaluate how P-gp activity changes in rats with CPT-11-induced gastrointestinal damage, as assessed by the absorption of digoxin (DGX), a typical P-gp substrate. Methods Male Sprague-Dawley rats were intravenously administered CPT-11 at a dose of 60 mg/kg/day for 4 days to induce gastrointestinal damage. Then, the rats were administered DGX orally (40 μg/kg), after some of them were orally administered clarithromycin (CAM; 10 mg/kg), a P-gp inhibitor. DGX (30 μg/kg) was administered intravenously to determine the bioavailability (BA). The rats’ DGX plasma concentration profiles were determined using LC-MS/MS. Results CPT-11 treatment decreased the maximum concentration (Cmax) and area under the plasma concentration-time curve (AUCpo) of DGX, which does not contradict to the DABE study. Although in the CPT-11-treated group the BA of DGX was significantly decreased to 40% of the control value, CAM did not affect the BA of DGX in the CPT-11-treated group. Conclusions Increased P-gp expression in rats with CPT-11-induced gastrointestinal damage is not necessarily associated with increased P-gp activity or contribution to the drug absorption in vivo. The decreased DGX absorption observed in this study might be attributable to other factors, such as a reduction in the absorptive surface area of the gastrointestinal tract.

Research/Practice Reports: Perspectives on Digoxin Absorption from Small Bowel Resections

Digoxin is a commonly prescribed medication for a variety of cardiovascular abnormalities. The therapeutic index of digoxin is considered narrow and drug is absorbed predominantly from the duodenum and upper jejunum. When the small intestine is intact, the absorption can vary; therefore, in the case of a small bowel resection or bypass, this erratic absorption may be accentuated. There is some controversy concerning the effect of small bowel resection or bypass on the absorption of digoxin. Some investigators have shown that small bowel resection or bypass decreases the absorption of oral digoxin, whereas others report no change in absorption. When the study methodologies were evaluated, certain common factors that support each view were found. In most studies reporting malabsorption, a solid dosage form of digoxin was used. Studies reporting no change in absorption investigated a solution dosage form.