Effect of genistein, a natural soy isoflavone, on the pharmacokinetics and intestinal toxicity of irinotecan hydrochloride in rats

Yokooji, Tomoharu; Kawabe, Yoshihiro; Mori, Nobuhiro; Murakami, Teruo

doi:10.1111/j.2042-7158.2012.01592.x

Cited by 12 publications

(8 citation statements)

References 32 publications

(41 reference statements)

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“…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, ; Kurita et al, ; Sezer et al, ; Takasuna et al, , , , ; Yokooji et al, ) The villous atrophication, shortening, and loss observed in the small intestines of the irinotecan group on day 5 (Figure ) were consistent with previous observations (Gupta et al, ; Saltz et al, ; Takasuna et al, ); 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, ; Kurita et al, ; Takasuna et al, ). Therefore, the protocol used in this study successfully produced an animal model of irinotecan‐induced gastrointestinal damage.…”

Section: Discussionsupporting

confidence: 87%

“…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).…”

Section: Discussionmentioning

confidence: 99%

“…Male Sprague-Dawley rats (Sankyo Labo Service Co., Inc., Tokyo), weighing 200-250 g (age 7 weeks), were allowed free access to food and water for 7 days before the irinotecan treatment. Irinotecan (60 mg/kg) was administered intravenously to the irinotecan group once a day for 4 days, as reported previously (Hu et al, 2006;Kurita et al, 2000;Sezer, Usta, & Cicin, 2009;Takasuna et al, 1995aTakasuna et al, , b, 1996Takasuna et al, , 2006Yokooji, Kawabe, Mori, & Murakami, 2013). Saline (3 ml/kg) was administered intravenously to the control group.…”

Section: Development Of An Animal Model and Evaluation Of Gastrointmentioning

confidence: 99%

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Irinotecan‐induced gastrointestinal damage impairs the absorption of dabigatran etexilate

Hattori

Imaoka

Akiyoshi

et al. 2019

Biopharm & Drug Disp

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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.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Development Of An Animal Model and Evaluation Of Gastrointmentioning

confidence: 99%

See 1 more Smart Citation

Irinotecan‐induced gastrointestinal damage impairs the absorption of dabigatran etexilate

Hattori

Imaoka

Akiyoshi

et al. 2019

Biopharm & Drug Disp

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“…Not many rodent studies up to now evaluated the same biomarkers of liver function after exposure to IRI, but they reported generally similar results [ 36 , 81 , 82 , 83 ]. The existing literature on serum markers of rodent hepatocellular damage after exposure to THC is inconsistent [ 38 , 39 , 40 , 41 , 63 , 64 , 84 ].…”

Section: Resultsmentioning

confidence: 94%

Irinotecan and Δ9-Tetrahydrocannabinol Interactions in Rat Liver: A Preliminary Evaluation Using Biochemical and Genotoxicity Markers

et al. 2018

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There is growing interest regarding the use of herbal preparations based on Cannabis sativa for medicinal purposes, despite the poorly understood interactions of their main constituent Δ9-tetrahydrocannabinol (THC) with conventional drugs, especially cytostatics. The objective of this pilot study was to prove whether the concomitant intake of THC impaired liver function in male Wistar rats treated with the anticancer drug irinotecan (IRI), and evaluate the toxic effects associated with this exposure. IRI was administered once intraperitoneally (at 100 mg/kg of the body weight (b.w.)), while THC was administered per os repeatedly for 1, 3, and 7 days (at 7 mg/kg b.w.). Functional liver impairments were studied using biochemical markers of liver function (aspartate aminotransferase—AST, alanine aminotransferase—ALP, alkaline phosphatase—AP, and bilirubin) in rats given a combined treatment, single IRI, single THC, and control groups. Using common oxidative stress biomarkers, along with measurement of primary DNA damage in hepatocytes, the degree of impairments caused at the cellular level was also evaluated. THC caused a time-dependent enhancement of acute toxicity in IRI-treated rats, which was confirmed by body and liver weight reduction. Although single THC affected ALP and AP levels more than single IRI, the levels of liver function markers measured after the administration of a combined treatment mostly did not significantly differ from control. Combined exposure led to increased oxidative stress responses in 3- and 7-day treatments, compared to single IRI. Single IRI caused the highest DNA damage at all timepoints. Continuous 7-day oral exposure to single THC caused an increased mean value of comet tail length compared to its shorter treatments. Concomitant intake of THC slightly affected the levels of IRI genotoxicity at all timepoints, but not in a consistent manner. Further studies are needed to prove our preliminary observations, clarify the underlying mechanisms behind IRI and THC interactions, and unambiguously confirm or reject the assumptions made herein.

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“…SN-38 is inactivated and detoxified to SN-38 glucuronide (SN-38G) primarily through glucuronidation by hepatic uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1). Most of CPT-11 and its metabolites are excreted into the intestinal lumen via bile, primarily mediated by multidrug resistance-associated protein-2 (MRP-2), breast cancer resistance protein (Bcrp), and P-glycoprotein (P-gp) (Yang et al, 2005 ; Bansal et al, 2009 ; Yokooji et al, 2013 ). The SN-38G that is excreted via bile is deconjugated by bacterial β-glucuronidase to SN-38, leading to the accumulation of SN-38 in the intestine.…”

Section: Introductionmentioning

confidence: 99%

Shengjiang Xiexin Decoction Alters Pharmacokinetics of Irinotecan by Regulating Metabolic Enzymes and Transporters: A Multi-Target Therapy for Alleviating the Gastrointestinal Toxicity

Guan

Wang

et al. 2017

Front. Pharmacol.

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Shengjiang Xiexin decoction (SXD), a classic traditional Chinese medical formula chronicled in Shang Han Lun, is used in modern clinical practice to decrease gastrointestinal toxicity induced by the chemotherapeutic drug irinotecan (CPT-11). In this study, the effect of SXD on the pharmacokinetics of CPT-11 and its active metabolites (SN-38 and SN-38G), and the underlying mechanisms were further examined. An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous quantification of CPT-11, SN-38, and SN-38G in the plasma, bile, liver, intestine, and intestinal contents of control and SXD-pre-treated rats after intravenous administration of CPT-11. SXD pretreatment increased the area under the curve (AUC) and the initial plasma concentration (C0) of CPT-11 but decreased the plasma clearance (CL). The AUC and the maximum plasma concentration (Cmax) of SN-38 decreased, whereas the Cmax of SN-38G increased. Compared with that of the control group, the biliary excretion of CPT-11, SN-38, and SN-38G was inhibited. The CPT-11, SN-38, and SN-38G concentrations in the liver, intestine, and intestinal contents were different between the two groups. Furthermore, the hepatic expression of multidrug resistance-associated protein-2 (Mrp-2), P-glycoprotein (P-gp), and carboxylesterase 2 (CES2) was significantly down-regulated by SXD, while the hepatic and jejunal uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) expression was elevated. The hydrolysis of CPT-11 to SN-38 by CES and the glucuronidation of SN-38 to SN-38G by UGT were affected by liver and jejunum S9 fractions from rats pre-treated with SXD. Therefore, this study demonstrated for the first time that SXD could alter the pharmacokinetics of CPT-11 and its metabolites to alleviate CPT-11-induced diarrhea. And the underlying mechanism of drug interaction between CPT-11 and SXD involves decreasing hepatic Mrp-2 and P-gp expression and altering the activities of CES and UGT.

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Effect of genistein, a natural soy isoflavone, on the pharmacokinetics and intestinal toxicity of irinotecan hydrochloride in rats

Abstract: Intravenous genistein was effective in ameliorating CPT-11-induced late-onset diarrhoea, by suppressing MRP2-mediated biliary excretion of CPT-11 and its metabolites.

Cited by 12 publications

References 32 publications

Irinotecan‐induced gastrointestinal damage impairs the absorption of dabigatran etexilate

Irinotecan‐induced gastrointestinal damage impairs the absorption of dabigatran etexilate

Irinotecan and Δ9-Tetrahydrocannabinol Interactions in Rat Liver: A Preliminary Evaluation Using Biochemical and Genotoxicity Markers

Shengjiang Xiexin Decoction Alters Pharmacokinetics of Irinotecan by Regulating Metabolic Enzymes and Transporters: A Multi-Target Therapy for Alleviating the Gastrointestinal Toxicity

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