Center of Drug Metabolism and Pharmacokinetics, College of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China.
Center of Drug Metabolism and Pharmacokinetics, College of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China
Drug Metab Dispos. 2019 Jun;47(6):556-566. doi: 10.1124/dmd.118.085803. Epub 2019 Mar 28.
Generally, diabetes remarkably alters the expression and function of intestinal drug transporters. Nateglinide and bumetanide are substrates of monocarboxylate transporter 6 (MCT6). We investigated whether diabetes down-regulated the function and expression of intestinal MCT6 and the possible mechanism in diabetic rats induced by a combination of high-fat diet and low-dose streptozocin. Our results indicated that diabetes significantly decreased the oral plasma exposure of nateglinide. The plasma peak concentration and area under curve in diabetic rats were 16.9% and 28.2% of control rats, respectively. Diabetes significantly decreased the protein and mRNA expressions of intestinal MCT6 and oligopeptide transporter 1 (PEPT1) but up-regulated peroxisome proliferator-activated receptor (PPAR) protein level. Single-pass intestinal perfusion demonstrated that diabetes prominently decreased the absorption of nateglinide and bumetanide. The MCT6 inhibitor bumetanide, but not PEPT1 inhibitor glycylsarcosine, significantly inhibited intestinal absorption of nateglinide in rats. Coadministration with bumetanide remarkably decreased the oral plasma exposure of nateglinide in rats. High concentrations of butyrate were detected in the intestine of diabetic rats. In Caco-2 cells (a human colorectal adenocarcinoma cell line), bumetanide and MCT6 knockdown remarkably inhibited the uptake of nateglinide. Butyrate down-regulated the function and expression of MCT6 in a concentration-dependent manner but increased PPAR expression. The decreased expressions of MCT6 by PPAR agonist troglitazone or butyrate were reversed by both PPAR knockdown and PPAR antagonist 2-chloro-5-nitro--phenylbenzamide (GW9662). Four weeks of butyrate treatment significantly decreased the oral plasma concentrations of nateglinide in rats, accompanied by significantly higher intestinal PPAR and lower MCT6 protein levels. In conclusion, diabetes impaired the expression and function of intestinal MCT6 partly via butyrate-mediated PPAR activation, decreasing the oral plasma exposure of nateglinide.
一般来说，糖尿病会显著改变肠道药物转运体的表达和功能。那格列奈和布美他尼是单羧酸转运体 6（MCT6）的底物。我们研究了糖尿病是否会下调糖尿病大鼠中由高脂肪饮食和低剂量链脲佐菌素联合诱导的肠道 MCT6 的功能和表达及其可能的机制。我们的结果表明，糖尿病显著降低了那格列奈的口服血浆暴露量。糖尿病大鼠的血浆峰浓度和曲线下面积分别为对照组的 16.9%和 28.2%。糖尿病显著降低了肠道 MCT6 和寡肽转运体 1（PEPT1）的蛋白和 mRNA 表达，但上调了过氧化物酶体增殖物激活受体（PPAR）蛋白水平。单次肠灌流表明，糖尿病显著降低了那格列奈和布美他尼的吸收。MCT6 抑制剂布美他尼，但不是 PEPT1 抑制剂甘氨酰肌氨酸，显著抑制了大鼠中那格列奈的肠吸收。布美他尼共给药显著降低了大鼠中那格列奈的口服血浆暴露量。糖尿病大鼠的肠道中检测到高浓度的丁酸盐。在 Caco-2 细胞（人结直肠腺癌细胞系）中，布美他尼和 MCT6 敲低显著抑制了那格列奈的摄取。丁酸盐以浓度依赖的方式下调 MCT6 的功能和表达，但增加了 PPAR 的表达。PPAR 激动剂曲格列酮或丁酸盐对 MCT6 的下调表达可被 PPAR 敲低和 PPAR 拮抗剂 2-氯-5-硝基--苯甲酰胺（GW9662）逆转。4 周的丁酸盐处理显著降低了大鼠中那格列奈的口服血浆浓度，同时伴有肠道 PPAR 显著升高和 MCT6 蛋白水平显著降低。总之，糖尿病通过丁酸盐介导的 PPAR 激活部分损害了肠道 MCT6 的表达和功能，降低了那格列奈的口服血浆暴露量。
