Pharmacokinetic and pharmacodynamic interaction of vildagliptin and voglibose in Japanese patients with Type 2 diabetes.

OBJECTIVE: To assess the extent of pharmacokinetic and pharmacodynamic interaction between vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase IV (DPP-4) enzyme, and voglibose, an α-glucosidase inhibitor widely prescribed in Japan, when coadministered in Japanese patients with Type 2 diabetes. METHODS: In this open-label, randomized, 3-treatment, 3-period and 6-way crossover study, 24 Japanese patients with Type 2 diabetes received 50 mg vildagliptin twice daily; 50 mg vildagliptin twice daily co-administered with 0.2 mg voglibose three times daily; or 0.2 mg voglibose three times daily for 3 days in each period. Plasma concentrations of vildagliptin, DPP-4, glucagon-like peptide-1 (GLP-1), glucose, insulin, and glucagon were determined from blood samples collected at steady state. RESULTS: Exposure to vildagliptin 50 mg (area under the concentration-time curve from 0 to 12 hours (AUCτ,ss)) and maximum plasma concentration at steady state (Cmax,ss) was reduced by 23% and 34% respectively with co-administration of voglibose. The percentage of DPP-4 inhibition by vildagliptin remained unchanged when vildagliptin was given alone or co-administered with voglibose; maximum inhibition was 98.3 ± 1.4% (mean ± SD) for vildagliptin alone and 97.4 ± 1.1% with co-administration. Coadministration of vildagliptin and voglibose led to a greater increase in the active GLP-1 plasma concentration than did vildagliptin alone (geometric mean ratio 1.63 (90% CI, 1.30, 2.03), p = 0.0007). The combination of vildagliptin and voglibose also led to a significantly lower plasma glucose levels (p < 0.0001). CONCLUSIONS: Plasma vildagliptin levels were decreased when voglibose was co-administered, although DPP- 4 inhibition remained unchanged. Co-administration led to significantly better pharmacodynamic response compared with each treatment alone, including higher active GLP-1 and lower glucose levels. The results indicate that this coadministration may be beneficial in the clinical situation. Vildagliptin and voglibose treatments, alone or when co-administered, were well tolerated in Japanese patients with Type 2 diabetes.

Regulation of tissue-specific expression of renal organic anion transporters by hepatocyte nuclear factor 1 α/ß and DNA methylation.

We have reported previously that the kidney- and liver-specific expression of transporters in mice involves the coordinated regulation by hepatocyte nuclear factor 1 (HNF1) and DNA methylation. The present study was aimed at investigating the role of this cascade in the transcriptional regulation of renal organic anion transporters (OATs) yet to be characterized in human and mouse. Luciferase assays and electrophoretic mobility-shift assays demonstrated that HNF1α/ß enhances the promoter activity of OAT4/SLC22A11 via binding to the HNF1 motif located near the transcriptional start site (TSS). DNA methylation profiles of human OAT1, OAT3, OAT4, and urate transporter 1 (URAT1) were determined in human liver and kidney cortex by bisulfite sequencing. Most of the CpG dinucleotides around the TSSs of OAT1 and OAT3 were highly methylated in the liver compared with kidney cortex, being consistent with their tissue specificity, whereas the difference in the DNA methylation status was less remarkable between the two tissues for OAT4 and URAT1. Mouse Oat1 gene also contained CpG dinucleotides hypomethylated in the kidney and hypermethylated in the liver downstream its TSS, whereas two of the seven CpG dinucleotides around the TSS of mouse Oat3 were significantly methylated in the liver compared with the kidney. Taken together, these findings underscored the central role of HNF1α/ß in the transcriptional regulation of OATs and highlighted DNA methylation-dependent gene silencing as one of the mechanisms underlying the tissue-specific transactivation by this master regulator.

Transcriptional regulation of human and mouse organic anion transporter 1 by hepatocyte nuclear factor 1 alpha/beta.

Organic anion transporter 1 (OAT1/SLC22A6) is predominantly expressed in the proximal tubules of the kidney. Cumulative studies have shown its critical role in the tubular secretion of a variety of organic anions, including several clinically important drugs. In addition, OAT1 is also involved in the pharmacological effect of diuretics and the nephrotoxicity of antiviral drugs. In contrast to these functional characterizations, the regulatory mechanism of OAT1 expression is poorly understood. It was recently demonstrated that the expression of Oat1 was markedly reduced in the kidneys of hepatocyte nuclear factor 1alpha (Hnf1alpha)-null mice. However, in vitro evidence for the involvement of HNF1alpha and further analyses are required to illustrate the transcriptional regulation of OAT1 genes in more detail. Computational analysis of the potential transcription factor binding sites revealed that the HNF1-motif was conserved in the proximal-promoter region of human and mouse OAT1 genes. The mRNA expression of mouse organic anion transporter 1 was drastically reduced in Hnf1alpha-null mice compared with that in wild-type mice, which was consistent with a previous report (Maher et al., 2006). Forced expression of HNF1alpha alone or both HNF1alpha and HNF1beta enhanced the activity of human and mouse OAT1 promoters in the transactivation assays, whereas HNF1beta alone was not active. Mutations in the HNF1-motif significantly reduced this transactivation. Direct binding of HNF1alpha/HNF1alpha homodimer and HNF1alpha/HNF1beta heterodimer to the HNF1-motif found in the human OAT1 promoter was demonstrated by electrophoretic mobility shift assays. These results provide convincing evidence for the involvement of HNF1alpha/beta in the constitutive expression of human and mouse OAT1 in the kidney.