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Possible factor for nonlinear pharmacokinetics of TAK‐603, a new antirheumatic agent, in rats
Author(s) -
Tagawa Yoshihiko,
Miwa Kiyoshi,
Yamashita Kenji,
Tsukuda Ryoichi,
Yoshimura Yoshinobu,
Tanayama Shigeharu,
Tanigawara Yusuke
Publication year - 1999
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(199901)20:1<11::aid-bdd147>3.0.co;2-#
Subject(s) - pharmacokinetics , metabolite , pharmacology , in vivo , chemistry , metabolism , microsome , in vitro , distribution (mathematics) , active metabolite , nifedipine , drug , volume of distribution , biology , biochemistry , calcium , mathematical analysis , microbiology and biotechnology , mathematics , organic chemistry
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 14 C‐labeled TAK‐603 ([ 14 C]TAK‐603) was studied using rats as these resemble humans in their metabolic profiles. After intravenous injection of [ 14 C]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. Copyright © 1999 John Wiley & Sons, Ltd.