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Research ArticleArticle

Effect of Its Demethylated Metabolite on the Pharmacokinetics of Unchanged Tak-603, A New Antirheumatic Agent, in Rats

Yoshihiko Tagawa, Kiyoshi Miwa, Ryoichi Tsukuda, Yoshinobu Yoshimura, Shigeharu Tanayama and Yusuke Tanigawara
Drug Metabolism and Disposition April 1999, 27 (4) 495-501;
Yoshihiko Tagawa
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Kiyoshi Miwa
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Ryoichi Tsukuda
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Yoshinobu Yoshimura
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Shigeharu Tanayama
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Yusuke Tanigawara
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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

  • 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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Drug Metabolism and Disposition: 27 (4)
Drug Metabolism and Disposition
Vol. 27, Issue 4
1 Apr 1999
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Research ArticleArticle

Effect of Its Demethylated Metabolite on the Pharmacokinetics of Unchanged Tak-603, A New Antirheumatic Agent, in Rats

Yoshihiko Tagawa, Kiyoshi Miwa, Ryoichi Tsukuda, Yoshinobu Yoshimura, Shigeharu Tanayama and Yusuke Tanigawara
Drug Metabolism and Disposition April 1, 1999, 27 (4) 495-501;

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Research ArticleArticle

Effect of Its Demethylated Metabolite on the Pharmacokinetics of Unchanged Tak-603, A New Antirheumatic Agent, in Rats

Yoshihiko Tagawa, Kiyoshi Miwa, Ryoichi Tsukuda, Yoshinobu Yoshimura, Shigeharu Tanayama and Yusuke Tanigawara
Drug Metabolism and Disposition April 1, 1999, 27 (4) 495-501;
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