Irinotecan‐induced gastrointestinal damage impairs the absorption of dabigatran etexilate

Abstract

Irinotecan causes serious gastrointestinal damage. Dabigatran etexilate (DABE), an oral anticoagulant and substrate of P‐glycoprotein (P‐gp), is poorly absorbed and exhibits low bioavailability in humans. The aim of this study was to evaluate the effects of irinotecan‐induced gastrointestinal damage on the pharmacokinetics/pharmacodynamics (PK/PD) of DABE. Irinotecan was administered intravenously to rats for 4 days to induce gastrointestinal damage. To investigate the PK profile of dabigatran (DAB), an active moiety of DABE, DABE was administered orally on day 5, and then DAB was administered intravenously on day 6. To evaluate the PD profile of DAB, the activated partial thromboplastin time (APTT) was measured. The protein expression level of intestinal P‐gp was evaluated. In the irinotecan‐treated rats, the area under the concentration–time curve of DAB after the oral administration of DABE and the bioavailability of DABE were decreased significantly. The APTT ratio also decreased, suggesting that the impaired efficacy of DABE was attributable to a reduction in its bioavailability. The expression of intestinal P‐gp was higher in the irinotecan‐treated rats. Taking into consideration the histological damage caused to the intestinal epithelium, both the increased P‐gp expression and the reduced passive diffusion were considered to be responsible for the reduction in the bioavailability of DABE.

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

“…The mean diarrhea score of the CPT-11-treated group on day 4 was 2.2 while that of the control group was zero (Table 2 ). These results were comparable with those described in previous reports [ 10 – 14 ].

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“…After the administration of DGX alone, the C max , AUC po , and BA values of DGX were significantly lower in the CPT-11-treated group than in the control group, and these findings seem to be consistent with the results of our previous study of DABE [ 10 ]. However, CAM did not significantly affect the absorption kinetics of DGX in rats treated with CPT-11.…”

“…Body weight, food intake, the fecal count, and fecal weight were monitored during the 4-day administration period. On the day after the final dose of CPT-11 was administered (day 5), the state of the rats’ feces and the perianal staining were examined and scored according to the diarrhea score criteria (Table 1 ) [ 10 – 14 ].…”

“…These findings indicate that the tissue damage induced in the intestinal tract by anticancer drugs essentially involves the atrophication of the intestinal villi and intracellular space expansion. Besides alterations in passive absorption, we have reported that in rats the intestinal expression levels of transporters, such as peptide transporter 1 (Pept1), P-gp, and breast cancer resistance protein (Bcrp), are also affected by anticancer drugs [ 9 , 10 ]. Previously, we have demonstrated in rats that 5 days’ treatment with 5-FU (30 mg/kg/day) resulted in the 15-fold upregulation of P-gp expression and a 2.6-fold increase in Bcrp expression in the intestines, as demonstrated by Western blotting [ 9 ].…”

“…Previously, we have demonstrated in rats that 5 days’ treatment with 5-FU (30 mg/kg/day) resulted in the 15-fold upregulation of P-gp expression and a 2.6-fold increase in Bcrp expression in the intestines, as demonstrated by Western blotting [ 9 ]. We have also shown in rats in which gastrointestinal damage was induced using intravenous CPT-11 (60 mg/kg/day for 4 consecutive days) that the intestinal expression of P-gp was significantly increased to 2- to 5- fold higher than the control level [ 10 ]. In addition, the bioavailability (BA) of dabigatran etexilate (DABE), a P-gp substrate, decreased 6.25-fold, suggesting that the upregulation of P-gp was responsible for the reduced BA of DABE.…”