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

Journal of Pharmaceutical Health Care and Sciences

Toshiaki Tsuchitani¹  Ayuko Imaoka¹  Takeshi Akiyoshi¹  Hisakazu Ohtani¹ 

[1] Division of Clinical Pharmacokinetics, Keio University Faculty of Pharmacy, 1-5-30, Shibakoen Minato-ku, 105-8512, Tokyo, Japan;

关键词: Drug absorption;    P-gp;    Gastrointestinal damage;    Digoxin;    Clarithromycin;   

DOI  :  10.1186/s40780-021-00207-w

来源: Springer

【 摘 要 】

BackgroundIrinotecan (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.MethodsMale 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.ResultsCPT-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.ConclusionsIncreased 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.

【 授权许可】

CC BY