Decreased hepatobiliary transport of methotrexate in adjuvant arthritis rats.
1. We investigated the difference in hepatobiliary transport of methotrexate in normal and adjuvant arthritis (AA) rats and substantiated the expression level of multidrug resistance-associated protein 2 (MRP2) in the liver. 2. Biliary clearance of methotrexate in normal and AA rats was calculated from plasma concentrations and biliary excretion following intravenous infusion and hepatic uptake clearance was estimated from an integration plot using methotrexate concentrations in plasma and liver. 3. Biliary clearance of methotrexate in AA rats was 2.30 +/- 0.23 ml min(-1) kg(-1) (mean SD) and significantly lower than in normal rats (8.42 +/- 0.81 ml min(-1) kg(-1)). The uptake clearance of methotrexate in AA rats was also lower than in normal rats (0.138 versus 0.278 ml min(-1) g liver(-1)). 4. MRP2 in the liver was detected by fluorescein isothiocyanate-labelled antibody and visualized using a confocal laser microscope system. The expression level of MRP2 in AA rats was very low compared with normal rats, indicating a down-regulation in AA rats. 5. In conclusion, biliary clearance of methotrexate was decreased due to the lower activities in both uptake and canalicular secretion, suggesting that several active transporters in the liver, including MRP2, are down-regulated in AA rats.
Achira
M
M
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd, 2-2-50 Kawagishi Toda Saitama 335-8505, Japan.
Totsuka
R
R
Fujimura
H
H
Kume
T
T
D000818:Animals; D019540:Area Under Curve; D001169:Arthritis, Experimental / Q000188:drug therapy*; D002851:Chromatography, High Pressure Liquid; D015536:Down-Regulation; D005260:Female; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008727:Methotrexate / Q000493:pharmacokinetics*; D024101:Mitochondrial Proteins; D051381:Rats; D011917:Rats, Inbred Lew; D012269:Ribosomal Proteins / Q000096:biosynthesis*; D029701:Saccharomyces cerevisiae Proteins; D013997:Time Factors
D007166:Immunosuppressive Agents; C093947:MRP2 protein, S cerevisiae; D024101:Mitochondrial Proteins; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; D008727:Methotrexate