HPLC/MS法研究左旋黄皮酰胺及其代谢物在Beagle犬血浆中的药代动力学  

Pharmacokinetics of (-)-clausenamide and its major metabolite 6-hydroxyl-clausenamide in Beagle dogs by HPLC/MS

作　　者：宋敏[1] 钱文[2] 杭太俊[1] 张正行[1] 

机构地区：[1]中国药科大学药物分析教研室,江苏南京210009 [2]江苏省药品检验所,江苏南京210008

出　　处：《药学学报》2005年第10期940-944,共5页Acta Pharmaceutica Sinica

摘　　要：目的用HPLC/MS法研究左旋黄皮酰胺[(-)-clau]及其代谢物6-羟基-黄皮酰胺(6-OH-clau)在Beagle犬血浆中的药代动力学过程.方法Beagle犬灌胃左旋黄皮酰胺30 mg·kg-1,采集静脉血样,血浆经乙酸乙酯萃取分离后,用HPLC/MS选择性正离子检测内标(格列吡嗪,[M+H]+,m/z 446)法测定左旋黄皮酰胺([M+H]+,m/z298)及6-羟基-黄皮酰胺([M+H-H2O]+,m/z 296)的浓度,以甲醇-水-冰醋酸(60:40:0.8)为流动相,流速1.0mL·min-1.用3P97软件计算药代动力学参数.结果左旋黄皮酰胺和6-羟基-黄皮酰胺分别在1.0～200ng·mL-1和0.2～40.0 ng·mL-1线性关系良好(r＞0.999),萃取回收率均大于85%.原药及其代谢物的体内过程均符合二室模型;左旋黄皮酰胺及6-羟基-黄皮酰胺的Cmax分别为(21±10)ng·mL-1和(3.9±2.2)ng·mL-1;Tmax分别为(0.8±0.5)h和(1.3±0.5)h;T1/2α分别为(0.9±0.6)h和(1.4±0.6)h;T1/2β分别为(19±23)h和(13±12)h;AUC0.24h分别为(69±14)h·ng·mL-1和(12±7)h·ng·mL-1.结论Beagle犬灌胃左旋黄皮酰胺后迅速吸收,血药浓度一相消除很快,但末端消除较慢;其代谢物6-羟基-黄皮酰胺血药浓度经时过程与左旋黄皮酰胺相似,但血药浓度相对较小.Aim To establish a sensitive and accurate method to study the pharmacokinetics of （ - ）- clausenamide [ （ - ）-clau ] and its major metabolite 6-hydroxyl-clausenamide （6-OH-clau） in the plasma of the Beagle dog. Methods （ - ）-Clau was orally administered to six Beagle dogs at the dose of 30 mg· kg^-1, venous blood from front leg was sampled and plasma was separated for analysis. After extraction with ethyl acetate, the plasma samples were analyzed by HPLC/MS and the mobile phase was a mixture of methanol-water-acetic acid （60：40 ： 0. 8 ） at the flow rate of 1.0 mL·min^-1 The API-ES positive ion SIM detection was carried out for the detection of both （ - ）-clau （ [ M ＋ H ] ^＋ , m/z 298） and 6-On-clau （[M ＋H -H2O]^＋, m/z 296） with glipzide （glip） （[M ＋H]^＋, m/z 446） as internal standard. The pharmacokinetic parameters were calculated by 3P97 software. Results There was good linear relationship （r 〉 0. 999） between the SIM responses and the concentrations for （ - ）-clau and 6-OH-clau at the range from 1.0 to 200 ng ·mL^-1 and 0.2 to 40. 0 ng ·mL^-1 , respectively. The absolute recovery was greater than 85%. The plasma concentration-time curves of （ - ）-clau and 6-OH-clau were both best fitted to a two-compartment model. The C of （ - ）-clau and 6-OH-clau were （21 ± 10）ng ·mL^-1 and （3.9 ±2.2） ng ·mL^-1, Tmax were （0.8 ±0.5） h and （1.3 ±0.5） h, Tj/2o~ were （0. 9 ±0.6） h and （ 1.4 ±0.6） h, T1/2β were （19 ±23） h and （13 ± 12） h, AUG0-24h were （69 ± 14） h·ng·mL^-1 and （ 12 ±7） h ·ng·mL^-1 respectively. Conclusion The established HPLC/MS method was sensitive and specific for the determination of （ - ）-clau. It was shown that the absorption and first phase elimination of （ - ）-clau were very quick in Beagle dogs, but the terminal elimination was very slow. The plasma eoneentration profile of its major metabolite 6-OH-elau was similar to （ - ）-elau and the AUC was relatively small

关 键 词：左旋黄皮酰胺 6-羟基-黄皮酰胺 药代动力学 高效液相色谱/质谱法 

分 类 号：R917.101[医药卫生—药物分析学]