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

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.