Strugala G J, Elsenhans B, Forth W
Walther Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, D-80336, München, Germany.
Biochem Pharmacol. 2000 Apr 15;59(8):907-13. doi: 10.1016/s0006-2952(99)00394-9.
In the present investigation with rings of everted rat small intestine, amphiphilic amines such as local anaesthetics (e.g. lidocaine, procaine, tolycaine) were employed to study their effects on intestinal absorption of methyl alpha-D-glucoside, L-leucine, D-fructose, and 2-deoxy-D-glucose. All the amphiphilic amines tested, except for benzocaine, significantly inhibited Na(+)-dependent active uptake of methyl alpha-D-glucoside and L-leucine while leaving uptake of D-fructose (facilitated diffusion) and 2-deoxy-D-glucose (passive diffusion) unaffected. Increasing concentrations of lidocaine in the incubation medium inhibited the uptake of methyl alpha-D-glucoside (IC(50) approximately 3.5 mmol/L) and L-leucine (IC(50) approximately 6 mmol/L) in a dose-dependent manner. Complete reversibility of the inhibitory effect could only be achieved at short-term incubations (</=2 min) and low lidocaine concentrations (</=3 mmol/L), otherwise inhibition became partially irreversible. Uptake kinetics of methyl alpha-D-glucoside and L-leucine in the presence of lidocaine revealed a significant increase in the apparent Michaelis constant, leaving the maximal transport capacity essentially unaltered. Reducing the Na(+) concentration in the incubation medium aggravated inhibition by lidocaine of the uptake of methyl alpha-D-glucoside. Analysis of the inhibition kinetics by Dixon plots revealed a competitive interaction between Na(+) and the amphiphiles. However, phlorizin binding was not affected by lidocaine. Changing the pH of the incubation medium from 5.6 to 8.0 increased the inhibitory effect of the amphiphiles, which indicated that the non-ionised and, thus, more lipophilic form participates in the mechanism of inhibition. However, benzocaine, a rather lipophilic local anaesthetic with no aliphatic amino group, did not impair active uptake of methyl alpha-D-glucoside. Whether the amphiphilic amines act by their partition into the membrane matrix or directly interact with sodium binding sites remains to be elucidated, however.
在本次对外翻大鼠小肠肠段的研究中，使用了亲脂性胺类药物，如局部麻醉药（如利多卡因、普鲁卡因、托利卡因），来研究它们对α-D-甲基葡萄糖苷、L-亮氨酸、D-果糖和2-脱氧-D-葡萄糖肠道吸收的影响。除苯佐卡因外，所有测试的亲脂性胺类药物均显著抑制α-D-甲基葡萄糖苷和L-亮氨酸的Na⁺依赖性主动摄取，而对D-果糖（易化扩散）和2-脱氧-D-葡萄糖（被动扩散）的摄取无影响。孵育介质中利多卡因浓度的增加以剂量依赖性方式抑制α-D-甲基葡萄糖苷（IC₅₀约为3.5 mmol/L）和L-亮氨酸（IC₅₀约为6 mmol/L）的摄取。只有在短期孵育（≤2分钟）和低利多卡因浓度（≤3 mmol/L）下，抑制作用才能完全可逆，否则抑制会部分不可逆。在利多卡因存在下，α-D-甲基葡萄糖苷和L-亮氨酸的摄取动力学显示，表观米氏常数显著增加，而最大转运能力基本未改变。降低孵育介质中的Na⁺浓度会加重利多卡因对α-D-甲基葡萄糖苷摄取的抑制作用。通过Dixon图分析抑制动力学表明，Na⁺与两亲性药物之间存在竞争性相互作用。然而，根皮苷结合不受利多卡因影响。将孵育介质的pH从5.6变为8.0会增加两亲性药物的抑制作用，这表明非离子化且因此更具亲脂性的形式参与了抑制机制。然而，苯佐卡因是一种相当亲脂性的局部麻醉药，没有脂肪族氨基，它不会损害α-D-甲基葡萄糖苷的主动摄取。然而，亲脂性胺类药物是通过分配到膜基质中起作用还是直接与钠结合位点相互作用仍有待阐明。
