Effect of its demethylated metabolite on the pharmacokinetics of unchangedTAK-603, a new antirheumatic agent, in rats

A factor in the dose-dependent pharmacokinetics of ethyl 4-(3,4-dimethoxyph enyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-yl-methyl)quinoline-3-carboxylate (T AK-603) in rats was shown to be due to the inhibition of metabolic clearanc e of unchanged TAK-603 by its major metabolite, M-I, in other words, produc t inhibition. The effect of M-I on the metabolic clearance of TAK-603 was s tudied using rats continuously infused i.v. with this metabolite at rates o f 5.3 and 16.0 mg/h/kg, The total body clearance of TAK-603 was decreased r emarkably in M-I-infused rats, and the decline of total body clearance depe nded on the steady-state plasma concentrations of M-I. The effect of M-l ge nerated from the dosed parent drug on the plasma concentration-time profile of TAK-603 was investigated using bile-cannulated rats after i.v. injectio n of C-14-labeled TAK-603 at doses of 1 and 15 mg/kg. Elimination rates of TAK-603 from rat plasma increased in the bile-cannulated rats in which syst emic M-I levels were reduced by interrupting its enterohepatic circulation. To express, simultaneously, the relationships between TAK-603 and M-I in p lasma concentration-time profiles, a kinetic model based on the product inh ibition was developed for the bile-cannulated rats. A good agreement betwee n calculated curves and the observed concentrations of both TAK-603 and M-I was found at 1 and 15 mg/kg, and the calculated curves were drawn using co nstant parameters for the two dosages. These results show that the product inhibition by M-I is one factor responsible for the dose-dependent pharmaco kinetics of TAK-603 in rats.