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目的考察盐酸度洛西汀在大鼠各肠段的吸收特征。方法采用离体外翻肠囊法,以HPLC法测定不同浓度的盐酸度洛西汀在大鼠各肠段的吸收量,并分别计算吸收速率常数(ka)和表观渗透系数(Papp);同法考察了P-糖蛋白抑制剂(维拉帕米和环孢素A)对盐酸度洛西汀肠道吸收的影响。结果药物浓度对大鼠各肠段ka没有明显影响;ka按空肠、回肠、十二指肠、结肠依次减小,分别为(2.64±0.17)、(2.15±0.11)、(1.24±0.04)和(0.88±0.09).h-1,药物吸收符合一级动力学特征,吸收机制为被动扩散;Papp按空肠、回肠、十二指肠和结肠依次减小,分别为(5.59±1.69)×10-5、(4.88±1.38)×10-5、(3.08±1.05)和(2.66±0.70)×10-5cm·s-1;P-糖蛋白抑制剂对吸收没有明显影响。结论盐酸度洛西汀吸收窗比较长,适合制成肠溶制剂,也提示可以制成在肠道中缓释的制剂。
Objective To investigate the absorption characteristics of duloxetine hydrochloride in various intestine of rats. Methods The everted intestinal sac method was used to determine the absorption of duloxetine hydrochloride in different intestinal segments by HPLC. The absorption rate constant (ka) and apparent permeability coefficient (Papp) were calculated respectively. Method investigated the effect of P-glycoprotein inhibitors (verapamil and cyclosporin A) on intestinal absorption of duloxetine hydrochloride. Results The drug concentration had no significant effect on the ka of the intestine of rats. Ka decreased by jejunum, ileum, duodenum and colon in turn (2.64 ± 0.17, 2.15 ± 0.11, 1.24 ± 0.04, (0.88 ± 0.09) .h-1, the drug absorption was consistent with the first-order kinetic characteristics and the absorption mechanism was passive diffusion. Papp decreased in the order of jejunum, ileum, duodenum and colon, which were (5.59 ± 1.69) × 10 -5, (4.88 ± 1.38) × 10-5, (3.08 ± 1.05) and (2.66 ± 0.70) × 10-5cm · s-1 respectively; P-glycoprotein inhibitors had no significant effect on absorption. Conclusion Duloxetine hydrochloride has a longer absorption window and is suitable for enteric preparation. It also suggests that it can be prepared into sustained release in the intestine.