Results in the present study indicate that all MDR1 stably expressing cells have efflux activity for various P-gp substrates, and that interspecies differences and similarities of the P-gp substrate efflux activity may exist.

TAK-875 is a selective G-protein-coupled receptor 40 agonist in development for the treatment of type 2 diabetes mellitus. This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-875 following administration of a single oral dose of TAK-875 (25-800 mg) in 60 healthy volunteers. TAK-875 was eliminated slowly with a mean terminal elimination t(1/2) of approximately 28.1 to 36.6 hours. Systemic exposure of TAK-875 did not exhibit dose-proportional increases across the dose range evaluated due to a greater than proportional increase in exposure at doses greater than 200 mg. A preliminary food effect assessment indicated that coadministration of TAK-875 with a high-fat meal decreased C(max) of TAK-875 by 40% and AUC by 17%. Clinical adverse experiences were generally mild and transient. No dose-dependent pattern was observed. In healthy volunteers, no glucose-lowering effect and no increase in insulin or c-peptide secretion were evident following administration of TAK-875; the frequency of plasma glucose concentrations <70 mg/dL was similar in the TAK-875 and pooled placebo groups. TAK-875 was well tolerated in the study and has pharmacokinetic characteristics suitable for a once-daily regimen. The pharmacodynamic data support the notion that TAK-875, if effective in diabetic patients, may bear a low risk of hypoglycemia.

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ABSTRACT:CYP2C9 and CYP2C19 are clinically important drug-metabolizing enzymes. The expression level of CYP2C9 is much higher than that of CYP2C19, although the factor(s) responsible for the difference between the expression levels of these genes is still unclear. It has been reported that hepatocyte nuclear factor 4␣ (HNF4␣) plays an important role in regulation of the expression of liver-enriched genes, including P450 genes. Thus, we hypothesized that HNF4␣ contributes to the difference between the expression levels of these genes. Two direct repeat 1 (DR1) elements were located in both the CYP2C9 and CYP2C19 promoters. The upstream and downstream elements in these promoters had the same sequences, and HNF4␣ could bind to both elements in vitro. The transactivation levels of constructs containing two DR1 elements of the CYP2C9 promoter were increased by HNF4␣, whereas those of the CYP2C19 promoter were not increased. The introduction of mutations into either the upstream or downstream element in the CYP2C9 gene abolished the responsiveness to HNF4␣. We also examined whether HNF4␣ could bind to the promoter regions of the CYP2C9 and the CYP2C19 genes in vivo. The results of chromatin immunoprecipitation assays showed that HNF4␣ could bind to the promoter region of the CYP2C9 gene but not to that of the CYP2C19 promoter in the human liver. Taken together, our results suggest that HNF4␣ is a factor responsible for the difference between the expression levels of CYP2C9 and CYP2C19 in the human liver.

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