Abstract
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 (CLli) 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 (CLgu), 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 (Kt,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 (Ka) in HDG mice compared to CG mice. There was a significant (**p < 0.01) association between ITCZ dose and the change in CLgu (ΔCLgu, r= −0.790), the change in CLli (ΔCLli, r= −0.787) and the change in Kt,br (ΔKt,br, r = 0.727), while the association between ITCZ dose and the change in Ka (ΔKa) 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.
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