title: Use of a semi-physiological pharmacokinetic model to investigate the influence of itraconazole on tacrolimus absorption, distribution and metabolism in mice.
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-1tacrolimus only), low-dose group (LDG, taking tacrolimus with 12.5 mg kg-1ITCZ), medium-dose group (MDG, taking tacrolimus with 25 mg kg-1ITCZ) and high-dose group (HDG, taking tacrolimus with 50 mg kg-1ITCZ). 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.
authors.affiliation: a Department of Pharmaceutical Analysis , School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China.
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Lu
authors.affiliation: b Department of Pharmaceutics , School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China , and.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhan
authors.affiliation: c Department of Measurement and Control , School of Physics, Liaoning University , Shenyang , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: a Department of Pharmaceutical Analysis , School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China.
authors.forename: Kai-Shun
authors.initials: KS
authors.lastname: Bi
authors.affiliation: a Department of Pharmaceutical Analysis , School of Pharmacy, Shenyang Pharmaceutical University , Shenyang , China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Chen
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics; D004347:Drug Interactions; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics; D017964:Itraconazole / Q000493:pharmacokinetics*; D051379:Mice; D008954:Models, Biological; D011897:Random Allocation; D016559:Tacrolimus / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D017964:Itraconazole; D016559:Tacrolimus
keywords: Absorption; Distribution; drug–drug interaction; itraconazole; metabolism; tacrolimus