Possible factor for nonlinear pharmacokinetics of TAK-603, a new antirheumatic agent, in rats

Yoshihiko Tagawa, Kiyoshi Miwa, Kenji Yamashita, Ryoichi Tsukuda, Yoshinobu Yoshimura, Shigeharu Tanayama, Yusuke Tanigawara

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

A new antirheumatic, TAK-603, shows nonlinear pharmacokinetics in both animals and humans. To elucidate the mechanism of these nonlinear pharmacokinetics, in vivo and in vitro metabolism of 14C-labeled TAK-603 ([14C]TAK-603) was studied using rats as these resemble humans in their metabolic profiles. After intravenous injection of [14C]TAK-603 to rats at doses of 1, 5, and 15 mg kg-1, the total body clearance of unchanged drug decreased significantly with increasing dose, whereas the apparent distribution volume did not alter remarkably. Thus, saturation in the elimination processes was considered to be a factor responsible for the nonlinear pharmacokinetics. The disappearance of unchanged drug from the circulation, however, followed a dose-dependent first-order process, indicating that the nonlinearity observed was not merely due to saturation of the elimination capacity. In vitro studies using rat liver microsomes showed that TAK-603 competitively inhibited CYP-catalysed nifedipine oxidation and also that the demethylated metabolite M-I, the major metabolite in rats and humans, competitively inhibited the oxidation of nifedipine. These results suggested that inhibition by M-I of the metabolism of the parent drug (i.e. product-inhibition) may be the most likely factor responsible for the nonlinear pharmacokinetics of TAK-603.

Original languageEnglish
Pages (from-to)11-18
Number of pages8
JournalBiopharmaceutics and Drug Disposition
Volume20
Issue number1
DOIs
Publication statusPublished - 1999 Jan 1
Externally publishedYes

Keywords

  • Nonlinear pharmacokinetics
  • Product-inhibition
  • Rat
  • TAK-603

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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