Radler S, Wermeille M, Blaschke G
Institut für Pharmazeutische Chemie, Universität Münster, Germany.
Arzneimittelforschung. 1995 Oct;45(10):1086-92.
The preparative separation of dimetindene (CAS 5636-83-9) enantiomers was achieved by fractionated crystallization of the diastereomeric tartrate salts. HPLC on alpha-AGP (alpha 1-acid glycoprotein) was used for confirmation of the enantiomeric purity. After administration of the enantiomers to rats the AUC and Cmax of S(+) dimetindene and (-)N-demethyldimetindene were slightly increased. In agreement with the serum concentration data significantly more (-)N-demethyldimethindene was excreted into urine after administration of the individual enantiomers. S(+) dimetindene was metabolised to a lesser extent in vivo (see above) as well as in vitro in rat liver homogenate. After prior enzyme induction conversion of the enantioselectivity with respect to unmetabolised dimetindene occurred. 6-Methoxydimetindene, 6-hydroxydimetindene and 6-hydroxy-N-demethyldimetindene were synthesized. 6-Methoxydimetindene is likely to be a metabolite since the retention times of synthetic compound and the substance extracted from serum and urine are identical. The formation of 6-hydroxy-N-demethyldimetindene was proved for the first time by comparison of the mass spectra of metabolite isolated from in vitro incubations and synthetic compound after derivatisation with acetic anhydride.
通过非对映体酒石酸盐的分级结晶实现了二甲茚定（CAS 5636 - 83 - 9）对映体的制备分离。采用α-AGP（α1-酸性糖蛋白）上的高效液相色谱法来确认对映体纯度。给大鼠施用对映体后，S(+)二甲茚定和(-)N-去甲基二甲茚定的AUC和Cmax略有增加。与血清浓度数据一致，施用单个对映体后，显著更多的(-)N-去甲基二甲茚定排泄到尿液中。S(+)二甲茚定在体内（见上文）以及大鼠肝脏匀浆的体外实验中代谢程度较低。在预先进行酶诱导后，未代谢的二甲茚定的对映选择性发生了转变。合成了6-甲氧基二甲茚定、6-羟基二甲茚定和6-羟基-N-去甲基二甲茚定。6-甲氧基二甲茚定可能是一种代谢产物，因为合成化合物与从血清和尿液中提取的物质的保留时间相同。通过比较从体外孵育物中分离的代谢物与用乙酸酐衍生化后的合成化合物的质谱，首次证明了6-羟基-N-去甲基二甲茚定的形成。
