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

Abstract

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.

A Simple, Fast, Low Cost, HPLC/UV Validated Method for Determination of Flutamide: Application to Protein Binding Studies

“…The resulting linearity range in this study was determined to be between 0.027 µg/ml and 27 µg/ml. 6 HPLC analysis of flutamide in blood serum were also reported by Filip et al with linearity range of 12.5 -625 µg/Ml. 7 Although a HPLC/ UV method was amplified by Xu Chang-Jiang which could be employed for analysis of flutamide in blood with a good linearity area of 0.1-20 µg /ml, the method needs a very complex extraction procedure and high cost evaporation step.…”

“…This might be explained by presence of detector with superior sensitivity than ours. 6 System suitability tests Retention time for un-retained compound of our analysis was 1 min. Calculated Kˈ (A) values were 1.35 and 2.87 for acetanilide and flutamide respectively.…”

Estimation of Transporters Involved in the Hepatobiliary Transport of TA-0201CA Using Sandwich-Cultured Rat Hepatocytes from Normal and Multidrug Resistance-Associated Protein 2-Deficient Rats

“…Accordingly, NTCP and BSEP play an important role in hepatobiliary transport of not only endogenous bile salt but also xenobiotics. Although BSEP has been focused in terms of drug-endogenous bile salt interactions (Funk et al, 2001;Iwanaga et al, 2007), little attention has been given to drug-drug interactions via BSEP. It must be noted that BSEP can be a responsible transporter for drug-drug interactions, which increases intrahepatic exposure to drugs.…”

“…Canalicular transporters involved in the biliary secretion from hepatocytes into bile canaliculi include bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein (BCRP), and multidrug resistance 1 (MDR1). The drugdrug/endogenous substance interaction via these transporters causes unexpected toxicity and serious adverse effects (Funk et al, 2001;Iwanaga et al, 2007). In addition, systemic exposure to hepatic transporter substrates could be affected by genetic polymorphisms of the transporter, resulting in alteration of their pharmacological or toxicological actions (Nozawa et al, 2005;Ieiri et al, 2009).…”

The Rats Liver External Secretory Function in Blockade of Androgen Receptors With Flutamide

“…Флутамід метаболізується у гепатоцитах з утворенням активних проміжних продуктів [13], пригнічує перенесення таурохолевої кислоти у клітинах печінки. Блокатор і його основний метаболіт 2-гідроксифлутамід ви-кликають гальмування транспорту екзоген-ного таурохолату у гепатоцитах [14]. Відома значна фізіологічна роль жовчних кислот, як обов'язкових компонентів жовчі ссавців і спе-цифічних продуктів холестеринового обміну у гепатоцитах [3].…”