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

Abstract

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.

Irinotecan‐induced gastrointestinal damage alters the expression of peptide transporter 1 and absorption of cephalexin in rats

“…Indeed, Gly‐Sar decreased the gastrointestinal absorption of CEX by only ∼10%, suggesting that CEX is absorbed primarily by passive diffusion. We previously reported that irinotecan‐induced gastrointestinal damage in rats reduced the absorption rate of orally administered acetaminophen, a passive marker (Hattori et al., 2019), and the intestinal absorption of digoxin, a P‐gp substrate, administered with a P‐gp inhibitor, clarithromycin (Tsuchitani et al., 2021). Furthermore, in this study the decrease in BA of CEX by Gly‐Sar coadministration was similar between the irinotecan and the control groups.…”

“…In rats with irinotecan-or 5-FU-induced gastrointestinal damage, we found more than an 80% decrease in the bioavailability (BA) of dabigatran etexilate, a P-gp substrate, while the expression of P-gp increased in the upper intestine (Hattori et al, 2019;Tsujii et al, 2018;Yotsumoto et al, 2017). Furthermore, we reported that the gastrointestinal absorption of digoxin, a typical P-gp substrate, decreased in rats with irinotecan-induced gastrointestinal damage (Tsuchitani et al, 2021).…”

“…In rats with irinotecan‐ or 5‐FU‐induced gastrointestinal damage, we found more than an 80% decrease in the bioavailability (BA) of dabigatran etexilate, a P‐gp substrate, while the expression of P‐gp increased in the upper intestine (Hattori et al., 2019; Tsujii et al., 2018; Yotsumoto et al., 2017). Furthermore, we reported that the gastrointestinal absorption of digoxin, a typical P‐gp substrate, decreased in rats with irinotecan‐induced gastrointestinal damage (Tsuchitani et al., 2021). Although anticancer drugs have been shown to alter the expression of various transporters other than P‐gp, it currently remains unclear whether the altered expression of other transporters in the intestines also affects the absorption of the respective substrate drugs.…”

The Effects of Jabara Juice on the Intestinal Permeation of Fexofenadine

“…The determination of digoxin and digitoxin levels by LC-MS/MS was conducted according to a method previously reported by our group. 33) The concentrations of fexofenadine and digoxin were determined using an LC-MS/MS system consisting of a controller (CBM-20A, Shimadzu, Kyoto, Japan), a pump (LC-20AD, Shimadzu), a triple quadrupole mass spectrometer (LCMS-8050 or LCMS-8030, Shimadzu), and a column oven (CTO-20AC, Shimadzu). To determine the concentration of fexofenadine in a sample, the sample was separated using an octadecylsilane column (150×2.0 mm, 5C 18 -MS-II, Cosmosil, Nacalai Tesque) equipped with a guard column (50 × 2.0 mm, 5C 18 -MS-II, Cosmosil).…”