Ursodeoxycholate Restores Biliary Excretion of Methotrexate in Rats with Ethinyl Estradiol Induced-Cholestasis by Restoring Canalicular Mrp2 Expression

Autor: Yun Ju Kang, Hye-Young Chi, Im-Sook Song, Min-Koo Choi, Hye Hyun Yoo, Min Ju Kim, Mihwa Kwon, Chang-Koo Shim, Young A. Choi
Rok vydání: 2018
Předmět:
Male
0301 basic medicine
Administration
Oral

Pharmacology
Ethinyl Estradiol
ursodeoxycholate (UDCA)
intrahepatic cholestasis
multidrug resistance-associated protein (Mrp) 2
methotrexate (MTX)
biliary excretion clearance
lcsh:Chemistry
Bile flow
0302 clinical medicine
lcsh:QH301-705.5
Spectroscopy
Cholestasis
Multidrug resistance-associated protein 2
Ursodeoxycholic Acid
Ursodeoxycholate
General Medicine
Multidrug Resistance-Associated Protein 2
Computer Science Applications
Treatment Outcome
030211 gastroenterology & hepatology
medicine.drug
Down-Regulation
Hepatobiliary Elimination
Drug Administration Schedule
Article
Catalysis
Bile Acids and Salts
Inorganic Chemistry
03 medical and health sciences
Biliary excretion
In vivo
medicine
Animals
Physical and Theoretical Chemistry
Molecular Biology
business.industry
Organic Chemistry
medicine.disease
Rats
Methotrexate
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
ATP-Binding Cassette Transporters
business
Zdroj: International Journal of Molecular Sciences; Volume 19; Issue 4; Pages: 1120
International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 19, Iss 4, p 1120 (2018)
ISSN: 1422-0067
DOI: 10.3390/ijms19041120
Popis: 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.
Databáze: OpenAIRE