Possible factor for nonlinear pharmacokinetics of TAK-603, a new antirheumatic agent, in rats
| Autor: | Yoshihiko Tagawa, Kiyoshi Miwa, Yusuke Tanigawara, Ryoichi Tsukuda, Shigeharu Tanayama, Yoshinobu Yoshimura, Kenji Yamashita |
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| Rok vydání: | 1999 |
| Předmět: |
Male
medicine.medical_specialty Nifedipine Metabolic Clearance Rate Metabolite Pharmaceutical Science Administration Oral Pharmacology Models Biological chemistry.chemical_compound Pharmacokinetics In vivo Oral administration Internal medicine medicine Animals Pharmacology (medical) Drug Interactions Tissue Distribution Rats Wistar Chromatography High Pressure Liquid Dose-Response Relationship Drug General Medicine Metabolism Triazoles In vitro Rats Endocrinology Tocolytic Agents chemistry Nonlinear Dynamics Product inhibition Antirheumatic Agents Area Under Curve Injections Intravenous Microsomes Liver Quinolines Oxidation-Reduction medicine.drug |
| Zdroj: | Biopharmaceuticsdrug disposition. 20(1) |
| ISSN: | 0142-2782 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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