In vitro-in vivo correlation for low-clearance compounds using hepatocyte relay method.

In vitro-in vivo correlation (IVIVC) of intrinsic clearance in preclinical species of rat and dog was established using the hepatocyte relay method to support high-confidence prediction of human pharmacokinetics for low-clearance compounds. Good IVIVC of intrinsic clearance was observed for most of the compounds, with predicted values within 2-fold of the observed values. The exceptions involved transporter-mediated uptake clearance or metabolizing enzymes with extensive extrahepatic contribution. This is the first assay available to address low clearance challenges in preclinical species for IVIVC in drug discovery. It extends the utility of the hepatocyte relay method in addressing low clearance issues.

Pharmacological inhibition to examine the role of DGAT1 in dietary lipid absorption in rodents and humans.

Alterations in fat metabolism, in particular elevated plasma concentrations of free fatty acids and triglycerides (TG), have been implicated in the pathogenesis of Type 2 diabetes, obesity, and cardiovascular disease. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), a member of the large family of membrane-bound O-acyltransferases, catalyzes the final step in triacylglycerol formation. In the intestine, DGAT1 is one of the acyltransferases responsible for the reesterficiation of dietary TG. Following a single dose of a selective pharmacological inhibitor of DGAT1, PF-04620110, a dose-dependent inhibition of TG and vitamin A absorption postprandially was demonstrated in rodents and human subjects. In C57/BL6J mice, acute DGAT1 inhibition alters the temporal and spatial pattern of dietary lipid absorption. To understand the impact of DGAT1 inhibition on enterocyte lipid metabolism, lipomic profiling was performed in rat intestine and plasma as well as human plasma. DGAT1 inhibition causes an enrichment of polyunsaturated fatty acids within the TG class of lipids. This pharmacological intervention gives us insight as to the role of DGAT1 in human dietary lipid absorption.