5-Fluororacil–Induced Gastrointestinal Damage Impairs the Absorption and Anticoagulant Effects of Dabigatran Etexilate

Tsujii, Kazunari; Hattori, Tomoki; Imaoka, Ayuko; Akiyoshi, Takeshi; Ohtani, Hisakazu

doi:10.1016/j.xphs.2017.12.023

Cited by 5 publications

(9 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, in an experiment involving everted sacs prepared from upper intestinal segments from 5‐FU‐treated rats the uptake of digoxin, a typical P‐gp substrate, was decreased (Yotsumoto et al, ). In these 5‐FU‐treated rats, the BA of DABE was also decreased (Tsujii et al, ). Therefore, the increased P‐gp expression observed in the irinotecan‐treated rats in the current study might conceivably have been responsible for the impaired absorption of DABE.…”

Section: Discussionmentioning

confidence: 95%

“…An animal model of irinotecan-induced gastrointestinal damage was produced by intravenous administration of irinotecan at a dose of 60 mg/kg/day for 4 days, according to a previously reported protocol (Hu et al, 2006;Kurita et al, 2000;Sezer et al, 2009;Takasuna et al, 1995aTakasuna et al, , 1995bTakasuna et al, , 1996Takasuna et al, , 2006Yokooji et al, 2013) The villous atrophication, shortening, and loss observed in the small intestines of the irinotecan group on day 5 (Figure 1) were consistent with previous observations (Gupta et al, 1994;Saltz et al, 2000;Takasuna et al, 2006); i.e., flattened villi and an increase in cell debris were seen in the rat cecum, jejunum, or ileum, together with reductions in body weight and food intake and changes in the stool score (Hu et al, 2006;Kurita et al, 2000;Takasuna et al, 1996). Therefore, the T A B L E 2 PK parameters obtained after the oral administration of DABE or APAP and the intravenous administration of DAB or APAP As a result, the expression of P-gp was found to be significantly increased by oral 5-FU (Tsujii et al, 2018) along with the decrease in the BA value of DAB (Yotsumoto, Akiyoshi, Wada, Imaoka, & Ohtani, 2017). It should be noted, besides the difference in the administration route, that irinotecan has a cytotoxic mechanism completely different from that of 5-FU and may have caused unique gastrointestinal damage.…”

Section: Discussionmentioning

confidence: 95%

“…Indeed, we have already developed another rat model with gastrointestinal damage caused by direct exposure to orally administered 5‐FU and investigated the change in the absorption of co‐administered drug. As a result, the expression of P‐gp was found to be significantly increased by oral 5‐FU (Tsujii et al, ) along with the decrease in the BA value of DAB (Yotsumoto, Akiyoshi, Wada, Imaoka, & Ohtani, ). It should be noted, besides the difference in the administration route, that irinotecan has a cytotoxic mechanism completely different from that of 5‐FU and may have caused unique gastrointestinal damage.…”

Section: Discussionmentioning

confidence: 99%

“…The DAB concentrations were determined using LC‐MS/MS system according to our previous method (Tsujii et al, ) described below. Briefly, the plasma samples were analysed by the LC‐MS/MS system consisting of a triple quadrupole mass spectrometer (API3200; AB Sciex Japan K.K., Tokyo).…”

Section: Methodsmentioning

confidence: 99%

“…The DAB concentrations were determined using LC-MS/MS system according to our previous method (Tsujii et al, 2018) described below.…”

Section: Determination Of Dab Concentrations Using Lc-ms/msmentioning

confidence: 99%

See 4 more Smart Citations

Irinotecan‐induced gastrointestinal damage impairs the absorption of dabigatran etexilate

Hattori

Imaoka

Akiyoshi

et al. 2019

Biopharm & Drug Disp

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The DAB concentrations were determined using LC-MS/MS system according to our previous method (Tsujii et al, 2018) described below.…”

Section: Determination Of Dab Concentrations Using Lc-ms/msmentioning

confidence: 99%

See 3 more Smart Citations

Irinotecan‐induced gastrointestinal damage impairs the absorption of dabigatran etexilate

Hattori

Imaoka

Akiyoshi

et al. 2019

Biopharm & Drug Disp

Self Cite

View full text Add to dashboard Cite

show abstract

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

Imaoka

Hattori

Akiyoshi

et al. 2023

Biopharm & Drug Disp

Self Cite

View full text Add to dashboard Cite

Irinotecan causes severe gastrointestinal damage, which may affect the expression of intestinal transporters. However, neither the expression of peptide transporter 1 (Pept1) nor the pharmacokinetics of Pept1 substrate drugs has been investigated under irinotecan‐induced gastrointestinal damage. Therefore, the present study quantitatively investigated the effects of irinotecan‐induced gastrointestinal damage on the intestinal expression of Pept1 and absorption of cephalexin (CEX), a typical Pept1 substrate, in rats. Irinotecan was administered intravenously to rats for 4 days to induce gastrointestinal damage. The expression of Pept1 mRNA and the Pept1 protein in the upper, middle, and lower segments of the small intestine of irinotecan‐treated rats was assessed by quantitative real‐time polymerase chain reaction (PCR) and western blotting, respectively. The pharmacokinetic profile of CEX was examined after its oral or intravenous administration (10 mg/kg). In irinotecan‐treated rats, ∼2‐fold increases in Pept1 protein levels were observed in all three segments, whereas mRNA levels remained unchanged. The oral bioavailability of CEX significantly decreased to 76% of that in control rats. The decrease in passive diffusion caused by intestinal damage may have overcome the increase in Pept1‐mediated uptake. In conclusion, irinotecan may decrease the intestinal absorption of Pept1 substrate drugs; however, it increased the expression of intestinal Pept1.

show abstract

Direct oral anticoagulants for the treatment and prevention of venous thromboembolism in patients with cancer: current evidence

et al. 2020

View full text Add to dashboard Cite

Venous thromboembolic disease (VTED) is a common and clinically important complication in patients with cancer, contributing to its mortality and morbidity. Direct oral anticoagulant agents (DOACs), including direct thrombin inhibitors and direct factor Xa inhibitors, are as effective as vitamin K antagonists for the treatment of VTED and are associated with less frequent and severe bleeding. They have advantages over low-molecular-weight heparin, but comparative long-term efficacy and safety data are lacking for these compounds. Recent randomized clinical trials suggest a role for DOACs in the treatment of VTED in patients with cancer. This review will discuss the existing evidence and future perspectives on the role of DOACs in the treatment of VTE based on the current evidence about their overall efficacy and safety and the limited information in patients with cancer; in addition, we will briefly review their pharmacokinetic properties with special reference to potential interactions.

show abstract

5-Fluororacil–Induced Gastrointestinal Damage Impairs the Absorption and Anticoagulant Effects of Dabigatran Etexilate

Cited by 5 publications

References 13 publications

Irinotecan‐induced gastrointestinal damage impairs the absorption of dabigatran etexilate

Irinotecan‐induced gastrointestinal damage impairs the absorption of dabigatran etexilate

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

Direct oral anticoagulants for the treatment and prevention of venous thromboembolism in patients with cancer: current evidence

Contact Info

Product

Resources

About