Regulation of paracellular absorption of cimetidine and 5-aminosalicylate in rat intestine.
Regulation of paracellular absorption of cimetidine and 5-aminosalicylate in rat intestine.
复制标题
西咪替丁和 5-氨基水杨酸盐在大鼠肠道内细胞旁吸收的调节。
DOI：
10.1023/a:1018974519984
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发表时间：
1999
影响因子：
3.7
通讯作者：
Fleisher,D
中科院分区：
文献类型：
--
作者：
Zhou,SY;Piyapolrungroj,N;Pao,L;Li,C;Liu,G;Zimmermann,E;Fleisher,D
目的.分离平行的跨细胞和细胞旁转运对小亲水性分子的肠吸收的相对贡献已被实验证明具有挑战性。在这篇报告中，药物代谢产物的管腔外观被用作一种工具，以评估细胞旁转运对西咪替丁和5-氨基水杨酸（5ASA）在大鼠小海马中吸收的贡献。本文研究了西咪替丁和5-氨基水杨酸在大鼠单次小肠灌流中的稳态吸收和消除。两种药物均在肠上皮细胞中代谢，随后代谢产物分泌到肠腔中。随着灌流浓度的增加，空肠对西咪替丁的吸收减少，而肠内代谢产物与肠内药物损失的比率增加。在灌注浓度高于0.4 mM时，西咪替丁的摄取导致超过80%的药物消除到空肠腔中。甲巯咪唑对西咪替丁细胞内代谢的抑制并不改变上皮细胞的摄取，但完全消除了西咪替丁的跨上皮通量，表明细胞内西咪替丁的升高。同样地，5 ASA与西咪替丁和他巴唑的共灌注完全消除了5 ASA的吸收，但增加了腔内N-乙酰基5 ASA的水平，表明细胞内5 ASA的摄取增加。西咪替丁和5ASA通过大鼠空肠上皮的吸收完全是细胞旁的。从质量平衡考虑推断，细胞内西咪替丁的升高限制了两种药物的细胞旁转运。
Purpose. Isolating the relative contributions of parallel transcellular and paracellular transport to the intestinal absorption of small hydrophilic molecules has proven experimentally challenging. In this report, lumenal appearance of drug metabolite is utilized as a tool to assess the contribution of paracellular transport to the absorption of cimetidine and 5-aminosalicylate (5ASA) in rat small intestine.Methods. Steady-state intestinal absorption and elimination of cimetidine and 5ASA were studied in single-pass intestinal perfusions in rats.Results. Both drugs were metabolized in intestinal epithelia with subsequent metabolite secretion into the intestinal lumen. Jejunal cimetidine absorption decreased with increasing perfusion concentration while the ratio of lumenal metabolite to lumenal drug loss increased. Cimetidine uptake at perfusion concentrations above 0.4 mM resulted in over 80% drug elimination into the jejunal lumen. Inhibition of intracellular metabolism of cimetidine by methimazole did not alter epithelial uptake but totally abolished transepithelial cimetidine flux indicating an elevation of intracellular cimetidine. Similarly, co-perfusion of 5ASA with cimetidine and methimazole totally abolished 5ASA absorption but increased lumenal levels of N-acetyl 5ASA indicating an increase in intracellular uptake of 5ASA.Conclusions. Cimetidine and 5ASA absorption across rat jejunal epithelia are exclusively paracellular. Elevation of intracellular cimetidine, inferred from mass balance considerations, restricts paracellular transport of both drugs.