Establishment of correlation between in vitro enzyme binding potency and in vivo pharmacological activity: application to liver glycogen phosphorylase a inhibitors

The Journal of Pharmacology and Experimental Therapeutics
Li J YuDennis J Hoover

Abstract

In drug discovery, establishing a correlation between in vitro potency and in vivo activity is critical for the validation of the selected target and for developing confidence in the in vitro screening strategy. The present study developed a competition equilibrium dialysis assay using a 96-well dialysis technique to determine the intrinsic Kd for 13 inhibitors of human liver glycogen phosphorylase a (GPa) in the presence of liver homogenate to mimic the physiological environment. The results provided evidence that binding of an inhibitor to GPa was affected by extra cofactors present in the liver homogenate. A good correlation was demonstrated between the in vitro Kd determined under liver homogenate environment and free liver concentration of an inhibitor at the minimum efficacious dose in diabetic ob/ob mice. This study revealed important elements (such as endogenous cofactors missing from the in vitro assay and free concentration at the target tissue) that contributed to a better understanding of the linkage between in vitro and in vivo activity. The approach developed here may be applied to many drugs in pharmacology studies in which the correlation between in vitro and in vivo activities for the target tissue (such as sol...Continue Reading

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Citations

Jan 21, 2012·Journal of Pharmaceutical Sciences·Brendan J MurphyJoseph F Krzyzaniak
Apr 11, 2020·Clinical Pharmacology and Therapeutics·Rasmus Jansson-LöfmarkJohan Gabrielsson
Dec 30, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Sean EkinsH James Harwood
Jan 9, 2019·The Journal of Organic Chemistry·Bryan LiShu Yu

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