Effects Of Voriconazole On The Pharmacokinetics Of Tacrolimus And Mechanisms Of Interaction Between These Two Drugs

Background:Tacrolimus is the substrate of CYP3A and P-gp,and voriconazole is the substrate and/or inhibitor of CYP3A and/or P-gp.These two drugs are commonly used in patients with fungal infection after kidney transplantation,which is bound to affect the efficacy and safety of tacrolimus.Objective:To clarify the quantitative influence of voriconazole on the pharmacokinetics of tacroimus,this study intends to investigate the mechanism of the interaction using enzymatic experiments and cell transport experiments.At the same time,in-vitro and in-vivo data were integrated to construct PBPK interaction model to quantitatively study the influence of CYP3A polymorphisms on the interaction between these two drugs,providing scientific basis for the individualization of tacrolimus dosage regimens.Methods:1.The content of tacrolimus in whole blood of rats was determined by HPLC-MS/MS under different dosage regimens（tacrolimus was given alone or in combination with voriconazole）.2.The CYP3A4/5 enzyme incubation system was established to explore the effects of voriconazole on CYP3A4/5 activity and the effects of voriconazole on tacrolimus metabolism through CYP3A4/5;3.The MDCKII-MDR1 cell model in vitro was constructed to explore the effect of voriconazole on transmembrane transport of tacrolimus and the effect of voriconazole on P-gp activity;4.Combined with experimental data and literature data,the PBPK model of drug-drug interaction（DDI）between tacrolimus and voriconazole was constructed and the influence of CYP3A5 polymorphisms on the DDI was predicted.Results:1.In a certain concentration range,the AUC of tacrolimus increased with the increase of voriconazole concentration.2.With the increase of voriconazole concentration,the residual amount of tacrolimus increased.And,the inhibition constant（K_i）of voriconazole on CYP3A4and CYP3A5 were（58.9±1.2）and（1.4±0.047）μM,respectively.3.Voriconazole had no significant effect on the uptake and transport of digoxin in MDCKII-MDR1 cells.With the increase of tacrolimus concentration,the permeability of the efflux chamber gradually decreased,and the efflux rate（ER）gradually decreased.4.The DDI PBPK model was successfully constructed.And,the predicted result showed that the C_maxand AUC_0-∞of tacrolimus in non-expressing CYP3A5 patients were 1.5 times and 1.93 times,respectively.Conclusions:The pharmacokinetic interaction between voriconazole and tacrolimus can significantly increase the blood concentration of tacrolimus in rats.The mechanism is mostly related to CYP3A4/5,but has no significant correlation with P-gp.In addition,voriconazole has a stronger inhibitory effect on CYP3A5 than CYP3A4.The results of model prediction suggested that the tacrolimus dose of CYP3A5 expresser should be about twice that of non-expressers.