盐酸法舒地尔在大鼠体内的吸收与分布

Absorption and distribution of fasudil and hydroxyfasudil after intragastric administration of fasudil hydrochloride to male Wistar rats

目的研究雄性Wistar大鼠灌胃盐酸法舒地尔的吸收和分布特征,为临床试验提供依据。方法大鼠分别灌胃和静注给予4 mg.kg-1盐酸法舒地尔后,采用液相色谱-串联质谱(LC-MS/MS)法测定血浆和组织中法舒地尔和羟基法舒地尔的浓度,用DAS 2.1.1软件计算主要药动学参数。结果灌胃给药后,大鼠血浆中法舒地尔和羟基法舒地尔的ρmax分别为(30.4±17.9)和(199±108)μg.L-1t,max分别为(0.3±0.1)和(0.7±0.7)h,AUC0-t分别为(53.3±13.7)和(434±223)μg.h.L-1t,1/2分别为(2.7±1.6)和(2.3±1.0)h,法舒地尔的绝对生物利用度为10.2%。组织分布试验表明,给药后0.25 h大部分组织中法舒地尔和羟基法舒地尔的浓度即达到峰值,6 h后各组织中的药物浓度均显著下降,法舒地尔主要分布在胃和小肠组织,其次在肝、脾等组织,羟基法舒地尔主要分布在肝组织,其次在胃、肠、肾等组织。结论大鼠灌胃盐酸法舒地尔后,在胃肠道迅速被吸收,并较快分布于全身各组织,血浆和组织中羟基法舒地尔的浓度明显高于法舒地尔的浓度,法舒地尔和羟基法舒地尔均没有组织蓄积现象。

Objective To study absorption and tissue distribution of fasudil and hydroxyfasudil after intragas- tric administration of fasudil hydrochloride to Wistar rats. Methods Fasudil hydrochloride （4 mg. kg - 1 ） was administrated by an i. g. and i. v. administration to Wistar rats. The concentration of fasudil and its active metabolite of hydroxyfasudil in rat plasma and tissues were detected by LC-MS/MS, the pharmacokinetic parameters were calculated by DAS 2. 1.1. Results The ρmax of both analytes were（30. 4 ± 17.9） and（ 199 ± 108）μg · L-1, tmax were （0.3 ± 0. 1 ） and （0.7 ± 0.7） h, AUC0.t were （53.3 ± 13.7） and （434± 223 ） μg·h-1 L - 1, t1/2 were （2. 7 ± 1.6 ） and （ 2. 3 ± 1.0） h, respectively. The absolute bioavailability of fasudil was 10. 2%. The concentration of fasudil and hydroxyfasudil in tissues were markedly after 0. 25 h following i. g. administration, and they were eliminated out after 6 h. Fasudil was mainly distributed in stomach and in- testine, secondly were in liver and spleen. Hydroxyfasudil was mainly distributed in liver, secondly were in stomach, intestine, kidney and so on. Conclusions Fasudil and hydroxyfasudil are immediately absorption and distribution after i. g. administration to rat, especially in the tissues with affluent blood. The concentration of fasudil and hydroxyfasudil are much higher than that of fasudil in plasma and tissues, and no accumulation is found.