非手性与手性色谱法研究尼莫地平及其对映体在大鼠体内的药代动力学及组织分布

目的研究尼莫地平及其对映体在大鼠体内药代动力学及组织分布特性。方法生物样品在碱性条件下,经正己烷-醋酸乙酯(1∶1)提取。非手性色谱分析用ODS柱(150 mm×4.6 mm ID),以甲醇-水(70∶30)为流动相;手性色谱分析用Chiralcel OJ柱(250 mm × 4.6 mm ID),以正己烷-无水乙醇(85∶15)为流动相;检测波长为236 nm。结果尼莫地平及其对映体分别在非手性及手性色谱系统中分离良好,在血浆及组织匀浆液中线性关系、最低检测限、精密度和准确度均满足分析要求。对映体间主要药动学参数T_max,C_max,AUC和CL_s,S-(-)-尼莫地平为:(2.1±0.3) h,(197±5) μg·L^-1,(656±18) μg·h·L^-1和(0.30±0.03) mL·min^-1,r-(+)-尼莫地平为:(1.7±0.5) h,(128±4)μg·L^-1,(381±8) μg·h·L^-1和(0.53±0.03) mL·min^-1;在主要的效应器官中S-(-)-尼莫地平的浓度高于r-(+)-尼莫地平,在主要消除器官中r-(+)-尼莫地平浓度高于S-(-)-尼莫地平的浓度。结论尼莫地平对映体在大鼠体内药代动力学及组织分布存在着立体差异性。

Studies on differences of pharmacokinetic behavior and tissue distribution of nimodipine and its two enantiomers in rats using achiral and chiral liquid chromatography

AIM: To investigate the differences of pharmacokinetic behavior and tissue distribution of nimodipine and its two enantiomers in rats. METHODS: A high-performance liquid chromatographic method with an ODS column (150 mm x 4.6 mm ID) and a mobile phase of methanol-water (70:30) was used for racemic nimodipine assay. Another method with a Chiralcel OJ column (250 mm x 4.6 mm ID) and a mixture of n-haxane-ethanol (85:15) as mobile phase was used to determine its two enantiomers. Nimodipine was monitored at 236 nm wavelength. RESULTS: The linearity, recoveries and the detection limits of the methods were found to be suitable for the determinations. The average results of within-day and between-day RSDs were 5.64% and 7.85% respectively, the mean recovery was 97.66% for the concentration ranges studied. The pharmacokinetic parameters Tmax, Cmax, AUC and CLs were: S-(-)-nimodipine (2.1 +/- 0.3) h, (197 +/- 5) microgram.L-1, (656 +/- 18) mL.min-1, (0.30 +/- 0.03) microgram.h.L-1, and R-(+)-nimodipine (1.7 +/- 0.5) h, (128 +/- 4) microgram.L-1, (381 +/- 4) mL.min-1, (0.53 +/- 0.03) microgram.h.L-1, respectively. The S-(-)-nimodipine concentration was 2.23 and 1.97 times as high as that of R-(+)-nimodipine in heart and in cerebrum respectively and there was almost only S-(-)-nimodipine in cerebellum. But R-(+)-nimodipine concentration was 1.57, 3.69 and 4.20 times as high as that of S-(-)-nimodipine in major excretion organs such as kidney, spleen and liver respectively. CONCLUSION: The experimental results obtained by using the achiral and chiral liquid chromatography showed that the differences between enantiomers were apparent for the pharmacokinetics in rat plasma, and very significant for the distributions in major target tissues: heart, cerebrum and cerebellum, and main elimination tissues: kidney, spleen and liver.