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, Yusuke Tanigawara

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)495-501
Number of pages7
JournalDrug Metabolism and Disposition
Volume27
Issue number4
Publication statusPublished - 1999

Fingerprint

Antirheumatic Agents
Pharmacokinetics
Metabolites
Rats
Bile
Plasmas
TAK 603
Enterohepatic Circulation
Injections
Kinetics

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Effect of its demethylated metabolite on the : Pharmacokinetics of unchanged TAK-603, a new antirheumatic agent, in rats. / Tagawa, Yoshihiko; Miwa, Kiyoshi; Tsukuda, Ryoichi; Yoshimura, Yoshinobu; Tanayama, Shigeharu; Tanigawara, Yusuke.

In: Drug Metabolism and Disposition, Vol. 27, No. 4, 1999, p. 495-501.

Research output: Contribution to journalArticle

Tagawa, Yoshihiko ; Miwa, Kiyoshi ; Tsukuda, Ryoichi ; Yoshimura, Yoshinobu ; Tanayama, Shigeharu ; Tanigawara, Yusuke. / Effect of its demethylated metabolite on the : Pharmacokinetics of unchanged TAK-603, a new antirheumatic agent, in rats. In: Drug Metabolism and Disposition. 1999 ; Vol. 27, No. 4. pp. 495-501.
@article{de690b9ce6f24d639e8753cc3cfe7441,
title = "Effect of its demethylated metabolite on the: Pharmacokinetics of unchanged TAK-603, a new antirheumatic agent, in rats",
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 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.",
author = "Yoshihiko Tagawa and Kiyoshi Miwa and Ryoichi Tsukuda and Yoshinobu Yoshimura and Shigeharu Tanayama and Yusuke Tanigawara",
year = "1999",
language = "English",
volume = "27",
pages = "495--501",
journal = "Drug Metabolism and Disposition",
issn = "0090-9556",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "4",

}

TY - JOUR

T1 - Effect of its demethylated metabolite on the

T2 - Pharmacokinetics of unchanged TAK-603, a new antirheumatic agent, in rats

AU - Tagawa, Yoshihiko

AU - Miwa, Kiyoshi

AU - Tsukuda, Ryoichi

AU - Yoshimura, Yoshinobu

AU - Tanayama, Shigeharu

AU - Tanigawara, Yusuke

PY - 1999

Y1 - 1999

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0032947119&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032947119&partnerID=8YFLogxK

M3 - Article

C2 - 10101145

AN - SCOPUS:0032947119

VL - 27

SP - 495

EP - 501

JO - Drug Metabolism and Disposition

JF - Drug Metabolism and Disposition

SN - 0090-9556

IS - 4

ER -