Differences in pharmacokinetics and hepatobiliary transport of a novel anti-inflammatory agent between normal and adjuvant arthritis rats.
1. The pharmacokinetics, particularly the hepatobiliary transport of T-5557 ((3-methyl-2-oxo-piperadin-3-yl)-acetic acid N'-(3-thieophen-2-yl-8-methoxy-quinazolin-1-yl)-hydrazide), a novel anti-inflammatory agent, has been examined in normal and adjuvant arthritis (AA) rats. 2. Following oral administration of T-5557, the absolute bioavailability in AA rats was increased by sixfold compared with normal rats. The extent of binding T-5557 to plasma proteins obtained from AA rats was markedly greater than in normal rats (97.0 versus 88.2%). The biliary clearance in AA rats was significantly lower than that in normal rats (1.186 versus 5.621 ml min(-1) kg(-1)), and lower intrinsic biliary clearance was also observed in AA rats (40.33 versus 69.83 ml min(-1) kg(-1)). 3. Concomitant administration of T-5557 with quinidine, a potent P-glycoprotein inhibitor, to normal rats caused a significant decrease in the biliary clearance of T-5557 by 37.9%. Moreover, the transport of T-5557 for the apical-to-basal compartment in a Caco-2 cells' monolayer was fourfold lower than that for the opposite direction, and was increased in the presence of quinidine and verapamil. 4. These results suggest that P-glycoprotein is involved in the biliary excretion of T-5557 and the decrease in the transport activity as well as the increase in plasma protein binding caused the elevated plasma concentration and bioavailability of T-5557 in AA rats.
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
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001169:Arthritis, Experimental / Q000188:drug therapy; D001692:Biological Transport; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008956:Models, Chemical; D011799:Quinazolines / Q000493:pharmacokinetics*; D011802:Quinidine / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors
C474690:(3-methyl-2-oxo-piperadin-3-yl)-acetic acid N'-(3-thieophen-2-yl-8-methoxy-quinazolin-1-yl)-hydrazide; D000893:Anti-Inflammatory Agents; D006834:Hydrazines; D011799:Quinazolines; D011802:Quinidine