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Title 

Model-based pharmacokinetic and pharmacodynamic analysis for acute effects of a small molecule inhibitor of diacylglycerol acyltransferase-1 in the TallyHo/JngJ polygenic mouse

Authors 

Y J ChaeJ S SongJ H AhnM A BaeKyeong-Ryoon Lee

Publisher 

Informa Healthcare

Issue Date 

2019

Citation 

Xenobiotica

Keywords 

Diacylglycerol acyltransferase 1 (DGAT-1)PF-04620110TallyHotriglyceridescholesterolpharmacokineticspharmacodynamicsmetabolism

Abstract 

1. The purpose of this study was to evaluate the acute effect of a small molecule inhibitor of DGAT-1 on triglycerides (TG) and cholesterol in polygenic type 2 diabetic TallyHo/JngJ (TH) mice. PF-04620110, a potent and selective DGAT-1 inhibitor, was used as a model compound in this study and which was administered to TH and ICR mice. 2. The concentration of the model compound that produced 50% of maximum lowering of TG level (IC50) in TH mice was not significantly different from that in ICR mice, when estimated using the model-based pharmacokinetic and pharmacodynamic assay, a two-compartmental model and an indirect response model. 3. The clearance of the inhibitor in TH mice was fivefold higher than that in ICR mice, suggesting significantly altered pharmacokinetics. Moreover, the in vitro metabolic elimination kinetic parameters (ke,met), determined using liver microsomes from TH and ICR mice were 1.24 ± 0.14 and 0.174 ± 0.116 min 1, respectively. 4. Thus, we report that the differences in the acute effects of the small molecule DAGT-1 inhibitor between TH mice and ICR mice can be attributed to altered pharmacokinetics caused by an altered metabolic rate for the compound in TH mice.

URI 

https://doi.org/10.1080/00498254.2018.1496303

ISSN 

0049-8254

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-07-10


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