Clinical utility of ursodeoxycholic acid in preventing flutamide‐induced hepatopathy in patients with prostate cancer: A preliminary study

Kojima, Munekado; Kamoi, Kazumi; Ukimura, Osamu; Fujito, Akira; Nakao, Masahiro; Tanaka, Shigeki; Miyashita, Hiroaki; Iwamoto, Noriyuki; Ohe, Hiroshi; Kitamori, Tomohito; Date, Seiki; Kitamura, Koji; Araki, Hirotaka; Aoki, Tadashi; Imada, Naoki; Takada, Hitoshi; Imaide, Y; Mikami, Kōichi; Uchida, Masaya; Saitoh, Masahito; Miki, Tsuneharu

doi:10.1046/j.1442-2042.2002.00412.x

Cited by 16 publications

(7 citation statements)

References 7 publications

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“…19,20) The FXR plays an important role in maintaining bile acid homeostasis by regulating key genes involved in bile acid synthesis, metabolism and transport, such as CYP7A1, UGT2B4, BSEP, NTCP, apical sodium bile acid cotransporter (ASBT), and organic solute transporter (OST) alpha-OSTbeta in humans. 28) Therefore, it may be possible that changes in the expression levels of these genes are involved in flutamide-induced cholestasis.…”

Section: Fig 5 Effect Of Flutamide On Expression Level Of (A) Rbsepmentioning

confidence: 99%

“…24) Furthermore, a similar pattern of the profile of flutamide metabolites was observed in the case of treatment with or without UDCA, 24) which is known to be beneficial for flutamide-induced hepatotoxicity. 19) However, it is possible that these metabolites inhibit Bsep-mediated bile acids transport. Therefore, these metabolites might be involved in flutamide-induced cholestasis in repeated-dose group.…”

Section: Fig 5 Effect Of Flutamide On Expression Level Of (A) Rbsepmentioning

confidence: 99%

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Involvement of Bile Salt Export Pump in Flutamide-Induced Cholestatic Hepatitis

Iwanaga

Nakakariya

Yabuuchi³

et al. 2007

Biological & Pharmaceutical Bulletin

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The non-steroidal antiandrogen flutamide is widely used for treatment of prostatic cancer, but causes side effects, including cholestatic hepatitis and fulminant hepatitis. We investigated the pathogenesis of flutamide-induced cholestatic hepatitis, focusing on the bile salt export pump (BSEP; ABCB11), which exports bile salts to the bile. We examined the inhibitory effects of flutamide and its active metabolite, hydroxyflutamide, on the transport of taurocholic acid (TCA) by membrane vesicles derived from hBSEP-expressing Sf9 cells. Flutamide inhibited the transport of TCA by hBSEP (IC50 value, about 50 microM), while hydroxyflutamide had no effect at up to 100 microM. When flutamide was administered to rats as a single oral dose of 100 mg/kg, the biliary excretion rate of bolus-injected [3H]TCA was decreased and the liver tissue concentration of flutamide exceeded 50 microM. Repeated doses of flutamide for 5 d (10 mg/kg/d) also decreased the biliary excretion rate of bolus-injected [3H]TCA. In this case, the liver tissue concentration of flutamide was below 0.1 microM. In both cases, no change in the mRNA level of rat Bsep was detected by RT-PCR. These results suggest that flutamide itself, but not its major metabolite, may cause cholestasis by inhibiting BSEP-mediated bile salt excretion.

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Section: Fig 5 Effect Of Flutamide On Expression Level Of (A) Rbsepmentioning

confidence: 99%

Section: Fig 5 Effect Of Flutamide On Expression Level Of (A) Rbsepmentioning

confidence: 99%

Involvement of Bile Salt Export Pump in Flutamide-Induced Cholestatic Hepatitis

Iwanaga

Nakakariya

Yabuuchi³

et al. 2007

Biological & Pharmaceutical Bulletin

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“…17,18) Since patient A presented with slight increases of AST and ALT levels during long-term flutamide treatment, he was treated with flutamide plus UDCA which resulted in the normalization of these serum clinical markers. To further assess the relationship between flutamide-induced hepatotoxicity and its metabolites, the metabolite profile of patient A treated with flutamide and UDCA was compared with that of patient A treated with flutamide alone.…”

Section: Metabolite Profiles Of Flutamide From Patients After Initialmentioning

confidence: 99%

Metabolite Profiles of Flutamide in Serum from Patients with Flutamide-Induced Hepatic Dysfunction

Takashima

Iguchi

Usui

et al. 2003

Biological & Pharmaceutical Bulletin

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Flutamide (2-methyl-N-[4-nitoro-3(trifluoromethyl)phenyl]propanamide) is a non-steroidal antiandrogen which behaves as a competitive agonist of the androgen receptor. 1-3)Flutamide is well recognized as a beneficial compound for the treatment of prostate cancer when used in combination with luteinizing hormone-releasing hormone agonists or orchiectomy. [4][5][6] This antiandrogen is also used in the treatment of hirsutism and benign prostatic hyperplasia. 7,8) Despite its proven utility, however, there has been growing concern about an association between flutamide and hepatotoxicity in humans. [9][10][11][12][13] Flutamide-induced hepatic dysfunction is considered to be a consequence of its biotransformation into electrophilic metabolites by cytochrome P450s (CYPs).14,15) These reactive metabolites likely bind to microsomal proteins, leading to either toxic or immune hepatitis in patients.14,15) Although a nitro anion free radical was found to be a reactive metabolite of a flutamide-related antiandrogen nilutamide, 16) the radical formation was not detected in the flutamide metabolites.14) Instead, flutamide was reported to be oxidatively metabolized by human CYP3A and 1A subfamilies into chemically reactive species, 14) but the causal metabolite for flutamide-induced hepatotoxicity has not yet been identified.Differences in frequencies of flutamide-related hepatotoxicity have been observed between reports from Japanese and Western patients. [9][10][11][12] Frequencies of hepatotoxicity in Western patients were reported to range from less than 1 to 10%.9,10) Despite the clinical dose of flutamide for Japanese patients being only half that for Westerners, a higher incidence of hepatotoxicity has been seen in the former group.11-13) The difference seems attributable to ethnic differences in the frequency of genetic polymorphism in drug metabolizing enzymes. If this view is correct, flutamide metabolites in the serum could be unique to the incidence group.It has been reported that elevated alanine aminotransferase (ALT) levels and past history of liver disorders were associated with an incidence of flutamide-induced hepatotoxicity. 12)Monitoring of serum aspartate aminotransferase (AST) and ALT levels during flutamide treatment is also known to be effective to obviate serious hepatotoxicity.10,12) Unfortunately, more specific predictors of which patients are at risk for flutamide-induced hepatotoxicity are not now available. If a measurement of flutamide metabolites in serum at the initial administration could predict those patients at risk for hepatotoxicity, the drug could be more comfortably used. In the present study, we screened the pattern of flutamide metabolites in serum from 15 patients administered flutamide, and the metabolite profiles from those showing hepatic dysfunction were compared with those from normal patients. Table 1. In three patients (A, B, C), hepatic dysfunction occurred after the start of flutamide treatment. Blood samples for determination of flutamide metabolites were collected before...

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“…Cardioprotection by definition includes all mechanisms and means that contribute to the preservation of the heart by reducing or preventing myocardial damage. It could lead to physiological adaptation or compensatory mechanism in reducing or preventing myocardial damage [118]. There is a vast range of cardioprotective drugs known to treat patient vulnerable to heart diseases.…”

Section: Cardioprotectionmentioning

confidence: 99%

Bile Acid Signaling and Cardioprotection

Hanafi¹,

As²,

Sh³

2018

Preprint

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Bile acids (BA) are classically known as an agent important in lipid absorption and cholesterol metabolism. Nowadays, BAs have been found to be involved in various cellular signaling pathways such as protein kinase cascades, cyclic AMP (cAMP) synthesis and calcium mobilization. In addition, they have also been shown to regulate glucose and energy homeostasis. Bile acids are ligands for several nuclear hormone receptors, including FXR. Recently, muscarinic receptor and TGR5, G-protein-coupled receptor (GPCR), have been suggested to play a role in bile acid activity which is independent of nuclear hormone receptors. Moreover, BAs have also been studied in other GPCR associated pathways, namely sphingosine-1-posphate and glucagon receptor. Hydrophobic bile acids have been proven to affect heart rate and its contraction. Elevated bile acids are associated with arrhythmias in adults and fetal heart. Altered ratios of primary and secondary bile acid are reported in chronic heart failure patients. Meanwhile in patients with liver cirrhosis, cardiac dysfunction has been strongly linked to the increase of serum bile acid concentrations. In contrast, the most hydrophilic BA known as ursodeoxycholic acid has been found beneficial in improving peripheral blood flow in chronic heart failure patients and protecting heart against reperfusion injury.

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Clinical utility of ursodeoxycholic acid in preventing flutamide‐induced hepatopathy in patients with prostate cancer: A preliminary study

Cited by 16 publications

References 7 publications

Involvement of Bile Salt Export Pump in Flutamide-Induced Cholestatic Hepatitis

Involvement of Bile Salt Export Pump in Flutamide-Induced Cholestatic Hepatitis

Metabolite Profiles of Flutamide in Serum from Patients with Flutamide-Induced Hepatic Dysfunction

Bile Acid Signaling and Cardioprotection

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