Effect of its demethylated metabolite on the pharmacokinetics of unchanged TAK-603, a new antirheumatic agent, in rats.
A factor in the dose-dependent pharmacokinetics of ethyl 4-(3, 4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2, 4-triazol-1-yl-methyl)quinoline-3-carboxylate (TAK-603) in rats was shown to be due to the inhibition of metabolic clearance of unchanged TAK-603 by its major metabolite, M-I, in other words, product inhibition. The effect of M-I on the metabolic clearance of TAK-603 was studied using rats continuously infused i.v. with this metabolite at rates of 5.3 and 16.0 mg/h/kg. The total body clearance of TAK-603 was decreased remarkably in M-I-infused rats, and the decline of total body clearance depended on the steady-state plasma concentrations of M-I. The effect of M-I generated from the dosed parent drug on the plasma concentration-time profile of TAK-603 was investigated using bile-cannulated rats after i.v. injection of 14C-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 systemic M-I levels were reduced by interrupting its enterohepatic circulation. To express, simultaneously, the relationships between TAK-603 and M-I in plasma concentration-time profiles, a kinetic model based on the product inhibition was developed for the bile-cannulated rats. A good agreement between 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 constant parameters for the two dosages. These results show that the product inhibition by M-I is one factor responsible for the dose-dependent pharmacokinetics of TAK-603 in rats.
Tagawa
Y
Y
Drug Analysis and Pharmacokinetics Research Laboratories, Pharmaceutical Development Division, Takeda Chemical Industries Ltd. Osaka, Japan. Tagawa_Yoshihiko@takeda.co.jp
Miwa
K
K
Tsukuda
R
R
Yoshimura
Y
Y
Tanayama
S
S
Tanigawara
Y
Y
D000818:Animals; D018501:Antirheumatic Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D001652:Bile Ducts / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D002404:Catheterization; D004305:Dose-Response Relationship, Drug; D007262:Infusions, Intravenous; D007700:Kinetics; D008297:Male; D008745:Methylation; D011485:Protein Binding; D011804:Quinolines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014230:Triazoles / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*
D018501:Antirheumatic Agents; D001798:Blood Proteins; D011804:Quinolines; D014230:Triazoles; C104411:TAK 603