Characterization of plasma protein binding in two mouse models of humanized liver, PXB mouse and humanized TK-NOG mouse

Abstract

The unbound fractions in plasma (f up) in two mouse models of humanized liver mice, PXB and humanized TK-NOG mice, were compared with human f up values using equilibrium dialysis method. A good relationship between f up values obtained from PXB mice and humans was observed; the f up of 34/39 compounds (87.2%) in PXB mice were within 3-fold of human f up. In contrast, a weak correlation was observed between human and humanized TK-NOG mouse f up values; the f up of 15/24 compounds (62.5%) in humanized TK-NOG mice were within 3-fold of human f up. As different profiles of plasma protein binding (PPB) profiles were observed between PXB and humanized TK-NOG mice, f up evaluation is necessary in each mouse model to utilize these humanized liver mice for pharmacological, drug–drug interaction (DDI), and toxicity studies. The unbound fraction in the mixed plasma of human and SCID mouse plasma (85:15) was well correlated with f up in PXB mice (38/39 compounds within a 3-fold). Thus, this artificial PXB mouse plasma could be used to evaluate PPB.