Use of a semi-physiological pharmacokinetic model to investigate the influence of itraconazole on tacrolimus absorption, distribution and metabolism in mice.

1. The aim of this study was to investigate the influence of itraconazole (ITCZ) on tacrolimus absorption, distribution and metabolism by developing a semi-physiological pharmacokinetic model of tacrolimus in mice. 2. Mice were randomly divided into four groups, namely control group (CG, taking 3 mg kg ^-1 tacrolimus only), low-dose group (LDG, taking tacrolimus with 12.5 mg kg ^-1 ITCZ), medium-dose group (MDG, taking tacrolimus with 25 mg kg ^-1 ITCZ) and high-dose group (HDG, taking tacrolimus with 50 mg kg ^-1 ITCZ). 3. Liver clearance (CL _li ) decreased significantly (**p < 0.01) in LDG (35.3%), MDG (45.2%) and HDG (58.7%) mice compared to CG mice. With respect to gut clearance (CL _gu ), significant (**p < 0.01) decrease was also revealed in LDG (35.9%), MDG (50.2%) and HDG (64.6%) mice. A significant (**p < 0.01) higher tacrolimus brain-to-blood partition coefficient (K _t,br ) was found in MDG (25.3%) and HDG (55.9%) mice than in CG mice. Moreover, a significant (*p < 0.05) increase (16.3%) was found in the absorption rate constant (K _a ) in HDG mice compared to CG mice. There was a significant (**p < 0.01) association between ITCZ dose and the change in CL _gu (ΔCL _gu , r= -0.790), the change in CL _li (ΔCL _li , r= -0.787) and the change in K _t,br (ΔK _t,br , r = 0.727), while the association between ITCZ dose and the change in K _a (ΔK _a ) was not significant (p > 0.05). 4. These findings could be useful in predicting the efficacy and toxicity of tacrolimus, and drug-drug interaction of ITCZ and tarcolimus in human.