Pharmacokinetic Evaluation Of The Drug Interaction Between Cyclosporine And Itraconazole In Rats

Objective: Aim to establish an analytical method in whole blood sample for both Cyclosporine (CsA) and Itraconazole (ICZ)by high-performance liquid chromatograph (HPLC).To evaluate the pharmacokinetics and the interaction between CsA microemulsion and ICZ oral solution in rats.Methods: Thirty male Sprague-Dawley rats were equally divided into three groups (A,B, and C) by random design according to weight. In the first stage , the rats in group A and B were intragastrically administered CsA (10 mg·kg^-1 (A₁)and ICZ(10mg·kg^-1 (B₁)separately , the rats in group C co-administered single-dose CsA and ICZ(10 mg·kg^-1 ),then blood samples (0.3～0.35mL) were collected from the tail at 0, 1, 2, 3, 4, 6, 8, 12, 24, 36,48 and72 h. In the second stage, CsA and ICZ(10 mg·kg^-1 )was separately treated to the rats in group A (A₂)and B(B₂) twice a day for 7days,the blood sample was collected at the 2th hour after every morning's intragastration and there was a extra sample collection for group A before every morning's intragastration .Day 8 ,both groups orally co-administered CsA and ICZ(10 mg·kg^-1 ). Blood samples were collected according to the schedule of the first stage. The whole blood concentration of CsA and ICZ was pretreated and determined by HPLC. Conditions:Shim—Pack C18((150mm×4.6mm,5μm))as analytical column, the mobile phase consisting of Acetonitrile : Water(76:24, V/V)at the flow rate of 1.0mL/min.TheUV detector was set at 210nm and the column was controlled at 68oC.Main pharmacokinetic parameters were calculated by DAS and compared by SPSS. Results: In group A₁,single oral dosing of CsA, T_max=1(h), t_1/2β=20.6±7.47 (h).As to group C (co-administrated immediately)and B2 (combined single dose of CsA with ICZ when ICZ approached the steady-state blood concentration),the AUC 0_-∞of CsA were increased from( 11.0±2.8)μg·h·mL^-1 to( 16.2±8.8)and( 21.5±5.7)μg·h·mL^-1 separately,increased by 47% and 95% (P <0.01). Compared with group A₁,the C_max of CsA in group B2 increased from(1.76±0.29)μg·mL^-1 up to(2.18±0.25)μg·mL^-1 , increased by 23.9%, (P<0.05).In group B₁,single oral dosing of ICZ, T_max=1(h), t_1/2β=11.26±1.43(h).As to group C (co-administrated immediately)and A2(combined single dose of ICZ with CsA when CsA approached the steady-state concentration),the AUC 0_-∞ of ICZ were increased from(4.2±2.9)μg·h·mL^-1 to( 5.5±4.5)μg·h·mL^-1,(P<0.05)and( 6.7±3.8)μg·h·mL^-1(P<0.01)separately, increased by 31% and 61%. Compared with group B₁, the mean Cmax of group A2 increased from(0.70±0.31)μg·mL^-1 to(0.94±0.43)μg·mL^-1 , increased by 34% (P<0.05).Conclusion: In rats, the co-administration of CsA and ICZ had significant mutual effects on many pharmacokinetic parameters. When one comes to the steady state concentration after multiple dose, the elimination half life of both drugs would significantly prolonged once co-administrated with the other one. Meanwhile the C_max and bioavailability would be remarkable improved. The bioavailability would also be increased when co-administrated at the first dose. It was indicated that the clinical dosage should be reduced when they were used together. There should be close therapeutic drug monitoring and dosage adjustment is necessary according to the monitoring results,in order to assure medication safety and promote their transplantation success rate.