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.