Pharmacokinetic disposition of anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in rats and dogs.

The pharmacokinetic disposition of anagliptin, an orally active and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated in male rats and dogs. Anagliptin was well absorbed in dogs (70.4 %) and moderately to well absorbed in rats ranging from 38.1 to 85.5 % depending on the dose. In situ testing indicated that anagliptin absorption from rat intestine was apparently limited by P-glycoprotein. The absorbed radioactivity was distributed rapidly throughout the body, and high levels of radioactivity were found in the tissues expressing DPP-4 at high levels, especially small intestine, kidney and liver. In both species, the major circulating component was unchanged anagliptin; major circulating metabolites were M1 resulting from hydrolysis of the cyano group and M6 and M7, both of which resulting from the oxidation-cleavage of the methylene function adjacent to the amine. After intravenous dosing, urinary excretion of radioactivity was the major route of elimination for rats (64.6 %) and dogs (66.2 %), and biliary excretion was demonstrated to be an important pathway in rats (25.2 %). The total recovery was good (97.5-99.5 %) and most of the radioactivity was excreted by 24 h in both species. The renal clearance of unbound anagliptin in rats (91.7 ml/min/kg) was much higher than the glomerular filtration rate, indicative of active renal elimination.

Real-time PCR-based method for the rapid detection of extended RAS mutations using bridged nucleic acids in colorectal cancer.

Mutations in RAS and BRAF are predictors of the efficacy of anti-epidermal growth factor receptor (EGFR) therapy in patients with metastatic colorectal cancer (mCRC). Therefore, simple, rapid, cost-effective methods to detect these mutations in the clinical setting are greatly needed. In the present study, we evaluated BNA Real-time PCR Mutation Detection Kit Extended RAS (BNA Real-time PCR), a real-time PCR method that uses bridged nucleic acid clamping technology to rapidly detect mutations in RAS exons 2-4 and BRAF exon 15. Genomic DNA was extracted from 54 formalin-fixed paraffin-embedded (FFPE) tissue samples obtained from mCRC patients. Among the 54 FFPE samples, BNA Real-time PCR detected 21 RAS mutations (38.9%) and 5 BRAF mutations (9.3%), and the reference assay (KRAS Mutation Detection Kit and MEBGEN™ RASKET KIT) detected 22 RAS mutations (40.7%). The concordance rate of detected RAS mutations between the BNA Real-time PCR assay and the reference assays was 98.2% (53/54). The BNA Real-time PCR assay proved to be a more simple, rapid, and cost-effective method for detecting KRAS and RAS mutations compared with existing assays. These findings suggest that BNA Real-time PCR is a valuable tool for predicting the efficacy of early anti-EGFR therapy in mCRC patients.

Synthesis and pharmacological characterization of potent, selective, and orally bioavailable isoindoline class dipeptidyl peptidase IV inhibitors.

Focused structure-activity relationships of isoindoline class DPP-IV inhibitors have led to the discovery of 4b as a highly selective, potent inhibitor of DPP-IV. In vivo studies in Wistar/ST rats showed that 4b was converted into the strongly active metabolite 4l in high yield, resulting in good in vivo efficacy for antihyperglycemic activity.