マウス肝ミクロソームにおけるDisopyramide光学異性体のN-脱アルキル化代謝の立体選択性

概要

論文の詳細を見る
The oxidative metabolism of disopyramide (DIS) enantiomers to mono-N-dealkyldisopyramide in mouse hepatic microsomes was studied in vitro. When (R-)-DIS was used as a substrate Lineweaver-Bulk plot was a single line with the apparent K_m value of 0.23 mM and V_<max> value of 1.05 nmol/mg protein/min. When S(+)-DIS was used as a substrate the plot was biphasic, and two apparent K_m values (K_<m_1>=0.04 and K_<m_2>=0.77,mM) and two V_<max> values (V_<max_1>=0.58 and V_<max_2>=1.53,nmol/mg protein/min) were obtained. When racemic DIS was used as a substrate the plot was also biphasic, while the plot observed at the lower concentration region was shifted to the upper region in comparison with that estimated from the sum of the individual N-dealkylase activities of each enantiomer. These results suggest that the N-dealkylation of R(-)-DIS is carried out by very limited cytochrome P-450 isozyme (s), but that of S(+)-DIS is carried out by multiple cytochrome P-450 isozymes ; that is, N-dealkylations of R(-)-and S(+)-DIS are involved in the different cytochrome P-450 isozymes each other, particularly at relatively higher concentration of the substrates.
公益社団法人日本薬学会の論文
1992-01-25