The Studies On Pharmacokinetics Of Ibudilast Sustained Release Capsules In Healthy Volunteers And Ibudilast Metabolism In Primarily Cultured Rat Hepatocytes

Objective: To study the pharmacokinetics of ibudilast sustained release capsule in healthy volunteers and the metabolism of ibudilast in isolated rat hepatocytes.Methods: LA single oral dose of 5 mg,10 mg and 20 mg of ibudilast sustained release capsule were given to 24 healthy volunteers in a randomized study. Ibudilast concentration in plasma was determined by HPLC method and cinnarizine(CNZ) was used as internal standard. The pharmacokinetic parameters of ibudilast were calculated by 3P97. 2.The metabolism of ibudilast in isolated rat hepatocytes was preliminary investigated. Hepatocytes were prepared from rats using two-step perfusion and collagenase digestion procedure, several different concentrations of ibudilast were incubated with hepatocytes. Aliquots of 2ml were withdrawn from the incubation mixture at different time points of incubation. The concentrations of ibudilast in hepatocyte suspension were determined by HPLC method and CNZ was used as internal standard. In addition, the yield and viability of hepatocytes were assessed by trypan blue exclusion and MTT method. The morphologic changes of cultured hepatocytes were observed.Results: l.The plasma concentration-time curves of ibudilast were fitted to the one compartment opened model with first-order absorption in a single dose of 5 mg and 10 mg groups. The main pharmacokinetic parameters of 5 mg and 10 mg group were: Tmax 1.63?.19 h and 1.58?.79 h , Cmax 17.39?5.23 ng/ml and 24.67?.31 ng/ml, AUC 102.77?3.77 (ng/ml)h and 143.66?5.06 (ng/ml)h, T1/2 5.43?.07 h and 4.45?.25 h respectively. The plasma concentration-time curves of ibudilast were fitted to the two compartment opened model with first-order absorption in a single dose of 20 mg groups. The main pharmacokinetic parameters were: Tmax 3.33?.58h, Cmax 56.39?-2-22.22ng/ml, AUC 622.66?85.44(ng/ml)h, T1/2 31.03?5.24 h. 2.The main pharmacokinetic parameters in isolated rat hepatocytes of 25ng/mL,50ng/mL and lOOng/mLgroups were: AUC 3736.68?136.55, 5363.02?07.01 30034.19?429.74 (ng/ml)min, T1/2 125.17?1.65, 89.95?.76 and 221.01?5.88min repectively. In the same cell concentration, the lower the concentration of Ibudilast, the faster the elimination is, and vice versa.Conclusion: 1. A single oral dose of Ibudilast were given to healthy volunteers, the peak concentration increased with dose gradually . The Tmax delayed and the rate of the elimination decreased with dose. 2. The dose and the elimination have a dose-dependant relation both in the experiments of rats in vitro and human in vivo. The saturation phenomenon may exist in the hepytocyte metabolism. The change of elimination rate may be the main reason of the change of the pharmacokinetic parameters.