Comparative Analysis of In Vitro and In Vivo Pharmacokinetic Parameters Related to Individual Variability of GTS-21 in Canine
-
- AZUMA Ryotaro
- Pharmacokinetics Research Lab, Taiho Pharmaceutical Co., Ltd.
-
- KOMURO Masahito
- Pharmacokinetics Research Lab, Taiho Pharmaceutical Co., Ltd.
-
- KAWAGUCHI Yasuro
- Pharmacokinetics Research Lab, Taiho Pharmaceutical Co., Ltd.
-
- OKUDAIRA Kazuho
- School of Pharmaceutical Sciences, Toho University
-
- HAYASHI Masahiro
- School of Pharmacy, Tokyo University of Pharmacy and Life Science
-
- KIWADA Hiroshi
- Faculty of Pharmaceutical Sciences, The University of Tokushima
この論文をさがす
抄録
To clarify the cause of the canine individual variability in plasma concentration after oral administration of GTS-21, we evaluated in vitro the metabolism to 4-OH-GTS-21 in liver microsomes of the same individuals from in vivo pharmacokinetic study. First, we applied to the Michaelis-Menten kinetic parameters to a dispersion model, and compared hepatic availability (FH) and hepatic clearance (CLH) values from in vitro with bioavailability (F), hepatic plasma flow (QPH), and plasma clearance (CLP) values from in vivo. The ratios of CLH to QPH were ranged 0.74 to 0.94, suggesting that GTS-21 is a hepatic plasma flow-limiting drug. A significant correlation of FH and F in the four dogs (r=0.995, p=0.005) indicates that the variability is predominantly caused by GTS-21 O4-demethylase activity. Second, we specified the cytochrome P450 (CYP) enzymes that are involved with the metabolism by chemical inhibition. α-Naphthoflavone, furafylline, quinidine, quinine, and troleandomycin significantly inhibited GTS-21 O4-demethylase activity. Thus CYP1A, CYP2D15, and CYP3A12 were involved with O4-demethylation. The variability in control activity decreased on addition of α-naphthoflavone and furafylline. Third, we quantified the contents of CYP1A and CYP3A12 by enzyme-linked immunosorbent assay. The content of CYP1A was consistent with GTS-21 O4-demethylase activity. We concluded that canine liver CYP1A causes the individual variability in GTS-21 plasma concentration after oral administration.<br>
収録刊行物
-
- Drug Metabolism and Pharmacokinetics
-
Drug Metabolism and Pharmacokinetics 17 (1), 75-82, 2002
日本薬物動態学会
- Tweet
詳細情報 詳細情報について
-
- CRID
- 1390001205179278720
-
- NII論文ID
- 10008198146
-
- NII書誌ID
- AA1162652X
-
- ISSN
- 18800920
- 13474367
-
- 本文言語コード
- en
-
- データソース種別
-
- JaLC
- Crossref
- CiNii Articles
-
- 抄録ライセンスフラグ
- 使用不可