Department of Pharmaceutical Technology, College of Pharmacy, University of Tanta, Tanta, Egypt.
Biopharm Drug Dispos. 2022 Dec;43(6):233-246. doi: 10.1002/bdd.2336. Epub 2022 Nov 7.
Lisinopril is an antihypertensive drug with poor intestinal permeability. Enhancement of intestinal absorption depends on a clear understanding of the permeation pathways and absorption mechanisms. Unfortunately, these are not fully elucidated for lisinopril. Accordingly, the aim was to determine lisinopril permeation pathways and obstacles limiting membrane transport with subsequent nomination of appropriate permeation enhancers. This employed an in situ rabbit intestinal perfusion technique, which revealed site-dependent absorptive clearance (PeA/L) from a lisinopril simple solution (5 μg/ml), with paracellular absorption playing a role. Regional drug permeability ranked as colon> duodenum> jejunum> ileum opposing intestinal expression rank of P-glycoprotein (P-gp) efflux transporters. Duodenal and jejunal perfusion of a higher lisinopril concentration (50 μg/ml) reflected saturable absorption, suggesting carrier-mediated transport. The effect of piperine and verapamil as P-gp inhibitors on intestinal absorption of lisinopril was investigated. Coperfusion with either piperine or verapamil significantly enhanced lisinopril absorption, with enhancement being dominant in the ileum segment. This supported the contribution of P-gp transporters to poor lisinopril permeability. On the other hand, coperfusion of lisinopril with zinc acetate dihydrate significantly multiplied lisinopril PeA/L by 2.3- and 6.6-fold in duodenum and ileum segments, respectively, through magnifying intestinal water flux. The study explored the barriers limiting lisinopril intestinal absorption. Moreover, the study exposed clinically relevant lisinopril interactions with common coadministered cargos that should be considered for an appropriate lisinopril regimen. However, this requires further in vivo verification.
赖诺普利是一种肠道通透性差的降压药。增强肠道吸收取决于对渗透途径和吸收机制的清晰理解。不幸的是，这些对于赖诺普利来说并没有完全阐明。因此，目的是确定赖诺普利的渗透途径和限制膜转运的障碍，随后提名适当的渗透增强剂。这采用了原位兔肠灌注技术，该技术显示了赖诺普利简单溶液（5μg/ml）的部位依赖性吸收清除率（PeA/L），其中细胞旁吸收起作用。区域性药物渗透性排名为结肠>十二指肠>空肠>回肠，与 P 糖蛋白（P-gp）外排转运体的肠表达顺序相反。十二指肠和空肠中更高浓度（50μg/ml）的赖诺普利灌注反映了可饱和的吸收，表明存在载体介导的转运。研究了胡椒碱和维拉帕米作为 P-gp 抑制剂对赖诺普利肠道吸收的影响。胡椒碱或维拉帕米的共灌注显著增强了赖诺普利的吸收，在回肠段增强作用占主导地位。这支持了 P-gp 转运体对赖诺普利低通透性的贡献。另一方面，在十二指肠和回肠段，二水合醋酸锌与赖诺普利共灌注分别使赖诺普利的 PeA/L 增加了 2.3 倍和 6.6 倍，这增加了肠内水通量。该研究探讨了限制赖诺普利肠道吸收的障碍。此外，该研究揭示了临床上相关的赖诺普利与常见共同给予的药物之间的相互作用，这应该考虑到适当的赖诺普利方案。然而，这需要进一步的体内验证。
