Diclofenac is an NSAID that is metabolized by CYP2C9 to 4′-hydroxy midazolam, UGT to the subsequent acyl glucuronide, and further by CYP2C8 to yield 4′-hydroxy midazolam acyl glucuronide. In mice, the clearance of this compound does not follow the clearance observed in human subjects. Midazolam is administered to human repopulated and non-repopulated FRG® KO mice which demonstrate a drastically different clearance when compared to each other. Further, when compared to known values for human in vivo clearance, highly humanized FRG® KO mice are capable of recapitulating the human situation.
Disappearance of diclofenac is measured in µg/mL in plasma and compared to clinical clearance data in the literature. Two non-repopulated FRG® KO mice are utilized as controls and demonstrate markedly less clearance than the four highly humanized models.