Abstract
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 of14C-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.
Footnotes
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Send reprint requests to: Dr. Yoshihiko Tagawa, Drug Analysis and Pharmacokinetics Research Laboratories, Pharmaceutical Development Division, Takeda Chemical Industries Ltd., 2–17-85, Juso-Honmachi, Yodogawa-ku, Osaka 532-8686, Japan. E-mail: Tagawa_Yoshihiko{at}takeda.co.jp
- Abbreviations used are::
- TAK-603
- ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-yl-methyl)-quinoline-3-carboxylate
- AUC
- area under the plasma concentration-time curve
- Km
- Michaelis-Menten constant
- Ki
- inhibition constants
- TLC
- thin-layer chromatography
- Vdc
- distribution volume of central compartment
- λ
- elimination rate constant
- CLtot
- total body clearance
- Cmax
- maximum concentration
- Received September 10, 1998.
- Accepted January 18, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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Effect of Its Demethylated Metabolite on the Pharmacokinetics of Unchanged Tak-603, A New Antirheumatic Agent, in Rats
