Wikberg T, Korkolainen T, Karlsson M
Orion-Farmos, Orion Research, Espoo, Finland.
Chirality. 1996;8(7):511-517. doi: 10.1002/(SICI)1520-636X(1996)8:7<511::AID-CHIR8>3.0.CO;2-D.
rac-Simendan, (+/-)-(R,S)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl ] hydrazono]propanedinitrile, and the levorotatory enantiomer levosimendan, are drug candidates intended for the treatment of congestive heart failure. An enantiospecific high-performance liquid chromatographic (HPLC) method suitable for determination of the ratio of the enantiomer concentrations in blood plasma samples was developed. Direct resolution of the enantiomers was achieved by using a chiral beta-cyclodextrin stationary phase in reversed phase mode. With an eluent containing 24-33% of methanol in a 0.5% (v/v) triethylammonium acetate buffer, pH 6.0, and a flow rate of 1 ml/min, a resolution (1.2-1.6) adequate for the determinations was achieved. By using UV detection, the relative concentration of the enantiomers in plasma was assessed down to 10 ng/ml. For the racemate, the results indicated a slightly enantioselective disposition and plasma protein binding in rat, dog, and man. The pure enantiomer, levosimendan, was found not to isomerize in vivo.
消旋西孟旦，(+/-)-(R,S)-[[4-(1,4,5,6-四氢-4-甲基-6-氧代-3-哒嗪基)-苯基]腙]丙二腈，以及左旋对映体左西孟旦，都是用于治疗充血性心力衰竭的候选药物。开发了一种对映体特异性高效液相色谱(HPLC)方法，适用于测定血浆样品中对映体浓度的比例。通过在反相模式下使用手性β-环糊精固定相实现了对映体的直接拆分。在pH 6.0的0.5%(v/v)醋酸三乙铵缓冲液中使用含24 - 33%甲醇的洗脱液，流速为1 ml/min，实现了足以进行测定的分离度(1.2 - 1.6)。通过紫外检测，血浆中对映体的相对浓度可低至10 ng/ml进行评估。对于外消旋体，结果表明在大鼠、狗和人体内有轻微的对映体选择性处置和血浆蛋白结合。发现纯对映体左西孟旦在体内不会异构化。
