RT Journal Article
SR Electronic
T1 Impairment of intestinal monocarboxylate transporter 6 function and expression in diabetic rats induced by combination of high-fat diet and low dose of streptozocin. Involvement of butyrate-PPARγ activation.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.085803
DO 10.1124/dmd.118.085803
A1 Feng Xu
A1 Liang Zhu
A1 Chaoqun Qian
A1 Junjie Zhou
A1 Donghao Geng
A1 Ping Li
A1 Wenjing Xuan
A1 Fangge Wu
A1 Kaijing Zhao
A1 Weimin Kong
A1 Yuanyuan Qin
A1 Limin Liang
A1 Li Liu
A1 Xiaodong Liu
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/03/28/dmd.118.085803.abstract
AB Generally, diabetes remarkably alters expression and function of intestinal drug transporters. Nateglinide and bumetanide are substrates of monocarboxylate transporter 6 (MCT6). We aimed to report that diabetes downregulated function and expression of intestinal MCT6 and to investigate the possible mechanism in diabetic rats induced by combination of high-fat diet and low dose of streptozocin. The results indicated that diabetes significantly decreased 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 protein and mRNA expressions of intestinal MCT6 and oligopeptide transporter 1 (PEPT1), but upregulated peroxisome proliferator-activated receptor-gamma (PPARγ) protein level. Single-pass intestinal perfusion (SPIP) demonstrated that diabetes prominently decreased absorption of nateglinide and bumetanide. MCT6 inhibitor bumetanide, but not PEPT1 inhibitor glycylsarcosine, significantly inhibited intestinal absorption of nateglinide in rats. Co-administration with bumetanide remarkably decreased oral plasma exposure of nateglinide in rats. High concentrations of butyrate were detected in intestine of diabetic rats. In Caco-2 cells, bumetanide and MCT6 knockdown remarkably inhibited uptake of nateglinide. Butyrate concentration-dependently downregulated function and expression of MCT6 but increased PPARγ expression. The decreased expressions of MCT6 by PPARγ agonist troglitazone or butyrate were reversed by both PPARγ knockdown and PPARγ antagonist GW9662. Four-week butyrate treatment significantly decreased oral plasma concentrations of nateglinide in rats, accompanied by significantly higher intestinal PPARγ and lower MCT6 protein levels. In conclusion, diabetes impaired expression and function of intestinal MCT6 partly via butyrate-mediated PPARγ activation, decreasing oral plasma exposure of nateglinide.