[Preparation of paraoxonase liposomes and their pharmacokinetics in rats].

Objective: To prepare paraoxonase 1 (PON1) liposomes, and investigate pharmacokinetics of common PON1 liposomes (L-PON1) and polyethylene glycol-modified PON1 long circulating liposomes (PEG-PON1-LCL) in rats after intravenous administration.

Methods: L-PON1 and PEG-PON1-LCL were prepared by film dispersion method. The entrapment efficiency, mean diameter and Zeta potential of the liposomes were measured, and the stability was evaluated. Thirty-six Wistar rats were divided into three groups according to random number table, with 12 rats in each group. The rats were intravenously administrated with PON1, L-PON1 or PEG-PON1-LCL 700 U/kg, respectively. The activity of PON1 in serum was determined by phenyl acetate method, the activity of PON1 at different time points after drug administration was compared with that before drug administration, and the difference value was considered as the activity of exogenous PON1, and PON1 activity-time curve was plotted. The pharmacokinetic parameters were calculated and analyzed by DAS 2.0 pharmacokinetic program and SPSS 17.0.

Results: The entrapment efficiencies of L-PON1 and PEG-PON1-LCL were above 85%, the mean diameter was about 126 nm, and Zeta potential was -14.35 mV. After 2 weeks of preservation, the above parameters showed no obvious change, indicating that liposomes had good stability and the properties of preparations were basically stable. Compared with purified PON1 administration, after L-PON1 and PEG-PON1-LCL administration, the activity of PON1 was increased, the half-life of PON1 activity in rats was significantly prolonged [the half-life of distribution (T, hours): 0.142±0.018, 0.147±0.021 vs. 0.126±0.022; the half-life of clearance (T, hours): 3.877±1.010, 4.520±1.117 vs. 1.226±0.422], the area under PON1 activity-time curve (AUC) was significantly increased [AUC from 0 hour to 24 hours (AUC, U×h×L): 499.305±64.710, 563.576±70.450 vs. 18.053±2.190; AUC from the immediate injection to the disappearance of PON1 activity (AUC, U×h×L): 516.256±60.940, 587.801±76.210 vs. 21.044±3.250], the apparent volume of distribution (Vd) and clearance (CL) were significantly decreased [Vd (L): 0.140±0.065, 0.144±0.064 vs. 0.493±0.032, CL (L/h): 0.039±0.008, 0.034±0.006 vs. 0.952±0.082, all P < 0.05]. There was no significant difference in pharmacokinetics between L-PON1 and PEG-PON1-LCL.

Conclusions: The film dispersion method prepared PON1 liposomes have high entrapment efficiency and small particle size with a good stability. Both liposomes can raise PON1 activity in vivo, change the pharmacokinetics of PON1 in vivo, prolong the resident time of PON1 in the blood circulating system, and compensate for the short half-life of PON1 in vivo.