盐酸戊乙奎醚外消旋体及其四个光学异构体在小鼠体内的分布与药代动力学

目的　研究盐酸戊乙奎醚外消旋体及其 4个光学异构体在小鼠体内的分布与药代动力学。方法　应用GC MS/SIM定量方法测定了盐酸戊乙奎醚外消旋体及其 4个光学异构体在小鼠脑、颌下腺及血浆中的药物浓度。结果　盐酸戊乙奎醚外消旋体在小鼠体内的血药时程符合一级吸收二室模型。其主要药动学参数为 :T1/ 2α0 2 3h ,T1/ 2 β3 2 8h ,T1/ 2Ka0 0 13h ,Tmax0 0 6 7h ,Cmax 18 76 μg·L-1,AUC5 0 4 2 μg·h·L-1。给药 8h后 ,盐酸戊乙奎醚外消旋体及其4个光学异构体在小鼠体内血药浓度存在差异。异构体R 2保持了相对较高的血药浓度。盐酸戊乙奎醚异构体在脑中的分布特点是与M受体亲和力较大的R 2异构体在脑中具有较高的分布浓度。R型异构体在脑中消除慢 ,而S型异构体在脑中消除快。盐酸戊乙奎醚在颌下腺中的分布特点为异构体S 1的分布浓度高 ,消除慢。结论　R及S型异构体在小鼠脑与颌下腺中的分布与mAChR的亲和力存在相关性。

Distribution and pharmacokinetics of penehyclidinehydrochloride raceme and its four optical isomers in mice

AIM To study the distribution and pharmacokinetics of penehyclidine hydrochloride(PH) raceme and its four optical isomers in mice. METHODS The tissue and blood concentration of PH raceme and its four optical isomers in mice were determined by gas chromatography mass spectrometry with selected ion monitoring(GC MS/SIM) PH(m/z 175) and PH 5 (m/z 180) as internal standard. RESULTS The concentration time curves in mice after im a single dose (0.1 mg·kg -1 ) could be fitted to first order absorption two compartments open model. The main pharmacokinetic parameters of PH raceme were as follows: T 1/2α 0.23 h, T 1/2β 3.28 h, T 1/2 K a 0.013 h, T max 0.067 h, C max 18.76 μg·L -1 , AUC 50.42 μg·L -1 . The speed of absorption and distribution of PH raceme in mice were fast.There were some differences for the level of the blood drug concentration of PH raceme and the four optical isomers within 8 hour after dosing the PH and four isomers, respectively. The R 2 isomer maintained a higher level of blood drug concentration compared with the other isomers. The drug concentration remained at a high level in submandibular glands and in brain for more than 48 h. The half life of PH in brain was 10.7 times greater than that in blood and 7.1 times greater than that in the submandibular glands. The distribution in mice brain showed that the concentration of R 2 isomer was high. And the isomer with S configuration in mice brain eliminated fast and isomer with R configuration eliminated slowly. The distribution in mice submandibular glands showed that the drug concentration of S 1 isomer had a high level and the elimination was slow. These findings suggest that S 1 isomer had a high affinity with mAChR in submandibular glands. CONCLUSION There is a close relationship between the concentration of the isomers in mice brain and submandibular gland and the affinity of the isomers to mAChR.