OCT3 promoter haplotype is associated with metformin pharmacokinetics in Koreans

Abstract

Organic cation transporter 3 (OCT3) is expressed in various organs in humans and plays an important role in the transport of organic cations and drugs including metformin. In this study, we identified genetic variations of the OCT3 promoter and functionally characterized each variant by in vitro assays. Next, the association between the functional haplotype of the OCT3 promoter and pharmacokinetics of metformin was evaluated. In our study population, 7 variations and 2 major haplotypes were identified, of which H2 haplotype yielded a significantly higher luciferase activity than did the wild type. Two variants of H2, c.-1603G > A and c.-1547T > G, yielded significantly lower luciferase activities, whereas the luciferase activity of another variant, c.-29G > A, was significantly higher. Two transcription factors, Sp1 and USF1, were involved in the regulation of OCT3 transcription. Analysis of clinical data revealed that 25 subjects, either homozygous or heterozygous for H2, showed increased AUCinf and Cmax by 17.2% and 15.9%, respectively [P = 0.016 and 0.031, GMR (90% CI) = 1.17 (1.06–1.29) and 1.17 (1.04–1.31), respectively], compared to the 20 subjects in the control group. Our study suggests that an OCT3 promoter haplotype affects the pharmacokinetics of metformin in Koreans as well as the OCT3 transcription rate.

Haplotypes of the Mutated SIRT2 Promoter Contributing to Transcription Factor Binding and Type 2 Diabetes Susceptibility

“…Promoter mutations may contribute to the alteration of transcriptional activity, expression dose, and phenotypic characteristics [28,29]. Kwon et al found that the OCT3 promoter haplotype H2 significantly affected luciferase activity as well as the metformin pharmacokinetics [30]. Our previous study reported that the T-A haplotype of the CREB1 gene exhibited maximal promoter activity, and resulted in susceptibility to T2D [14].…”

A Whole-Body Physiologically Based Pharmacokinetic Model Characterizing Interplay of OCTs and MATEs in Intestine, Liver and Kidney to Predict Drug-Drug Interactions of Metformin with Perpetrators

“…SNPs of OCT3 significantly affect intestinal absorption of metformin [ 66 , 67 ], demonstrating important roles of OCT3 in intestinal absorption of metformin, and some reports have showed that PMAT, OCT1 and SERT are involved in metformin transport in Caco-2 cells and other cell lines [ 11 , 28 , 51 ]. Based on data from OCT3 knockout mice and cell lines, we assumed that contribution of intestinal OCT3 and PMAT to intestinal absorption of metformin was about 50% and 20%, respectively, the rest (30%) was attributed to other transporters including THTR2, OCT1 and maybe SERT [ 6 , 7 , 66 , 67 ]. These results indicate that the intestinal absorption of metformin is mediated at least partly by OCT3 and PMAT expressed on apical membrane of enterocytes.…”

Structural basis of organic cation transporter-3 inhibition

“…Thus, the deeper knowledge of the structure and function of OCTs brings us closer to more precise and efficient medical treatments 22,41,42 . Therefore, our structures provide a new starting point for rational drug development targeting OCT3 in the treatment of depression 22,50 , diabetes 11,12,51 , cardiac disease 10,15 , and cancer chemotherapy 19,39,52 .…”

“…The herein investigated genetic variants 10,12,[35][36][37][38][39][40] were mapped on the structure of OCT3 (Fig. 4a) and functionally characterized in vitro (Fig.…”