Abstract
The in vivo relevance of ursodeoxycholate (UDCA) treatment (100 mg/kg/day, per oral tid for 5 days before cholestasis induction followed by the same dosing for 5 days) on hepatic function was investigated in rats with 17α-ethinylestradiol (EE, 10 mg/kg, subcutaneous for 5 days)-induced experimental cholestasis. The bile flow rate and the expression level of hepatic multidrug resistance-associated protein 2 (Mrp 2) that were decreased in cholestasis were restored after UDCA treatment. Consistent with this, the biliary excretion clearance (CLexc,bile) of a representative Mrp2 substrate—methotrexate (MTX)—was decreased in cholestatic rats but was restored after UDCA treatment. Consequently, the plasma concentrations of MTX, which were increased by cholestasis, were decreased to control levels by UDCA treatment. Thus, the restoration of CLexc,bile appears to be associated with the increase in Mrp2 expression on the canalicular membrane by UDCA treatment followed by Mrp2-mediated biliary excretion of MTX. On the other hand, the hepatic uptake clearance (CLup,liver) of MTX was unchanged by cholestasis or UDCA treatment, suggestive of the absence of any association between the uptake process and the overall biliary excretion of MTX. Since UDCA has been known to induce the expression of canalicular MRP2 in humans, UDCA treatment might be effective in humans to maintain or accelerate the hepatobiliary elimination of xenobiotics or metabolic conjugates that are MRP2 substrates.
Highlights
Ursodeoxycholate (UDCA), an endogenous hydrophilic bile salt, is predominant in bear bile and has been used as a traditional medicine for the treatment of jaundice
Sci. 2018, 19, 1120 elevated in the EE group, consistent with the induction of cholestasis and UDCA treatment restored the levels of these markers (Figure 1)
No change was observed in the level of blood urea nitrogen (BUN) and serum creatinine, indicative of the negligible impact of EE on kidney function
Summary
Ursodeoxycholate (UDCA), an endogenous hydrophilic bile salt, is predominant in bear bile and has been used as a traditional medicine for the treatment of jaundice. In 1989, the therapeutic efficacy of UDCA was re-demonstrated in the first clinical trials on patients with primary biliary cholangitis. UDCA has been marketed as a therapeutic for cholestasis and preventive drug for liver diseases [1,2]. Ursa® (Daewoong Pharmaceutical Co. Ltd., Seoul, Korea), a single tablet with 100–300 mg of UDCA, has been marketed in Korea since 1961 to cure liver diseases, including cholestasis. UDCA is the most widely prescribed drug for the treatment of cholestasis and the only medicine approved by the US Food and Drug Administration to treat primary biliary cirrhosis [2]
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