Decreased activity of hepatic P-glycoprotein in the isolated perfused liver of the adjuvant arthritis rat.
1. We investigated the hepatobiliary transport of doxorubicin in the isolated perfused liver prepared from the adjuvant arthritis rat, an animal model for rheumatoid arthritis, to examine the hepatic P-glycoprotein activity in the adjuvant arthritis rat. 2. Liver was isolated from the normal and the adjuvant arthritis rat and perfused for 60 min with recirculating buffer and the perfusate and bile samples were collected at timed interval. 3. The elimination of doxorubicin in the adjuvant arthritis rat tended to be reduced, but it was not significantly different from the normal rat. Biliary clearance (CL(bile)) in the normal rat was 1.93 +/- 0.48 ml min(-1), whereas, CL(bile) in the adjuvant arthritis rat was significantly decreased to 0.40 +/- 0.13 ml min(-1). 4. CL(bile) was markedly decreased to about 0.15 ml min(-1) in the presence of 100 microM verapamil in both types of rat. Methotrexate treatment had no effect on CL(bile) in both the normal and adjuvant arthritis rat (2.18 +/- 0.22 and 0.47 +/- 0.22 ml min(-1), respectively). 5. The results suggest that the hepatic P-glycoprotein activity was markedly decreased in the adjuvant arthritis rat and the effect of methotrexate on the hepatic P-glycoprotein activity did not corresponded to its anti-inflammatory effect.
Achira
M
M
Discovery Research Laboratory, Tanabe Seiyaku Co, Ltd, 2-2-50 Kawagishi Toda Saitama 335-8505, Japan. m-achira@tanabe.co.jp
Totsuka
R
R
Kume
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001168:Arthritis / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008727:Methotrexate / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D004317:Doxorubicin; D008727:Methotrexate