[The Pharmacokinetics and Pharmacodynamics of Intravenous Uricase Multivesicular Liposomes].

OBJECTIVE: To determine and compare the pharmacokinetics and pharmacodynamics of uricase-multivesicular liposomes (UOMVLs) with free uricase (UOX) in rats. METHODS: UOMVLs were prepared by the double emulsion method and confirmed with its entrapment efficiency, size and Zeta potential. Twelve healthy rats were randomly divided into two groups: one with i. v. injection of UOMVLs, and the other with i. v. injection of UOX. Their serum activity of uricase was assayed. The pharmacokinetic parameters were calculated using software DAS 2. 1. 1. Another 24 male SD rats were enrolled, the rat model of hyperuricemia was established with hypoxanthine and potassium oxonate, while normal group (n=6) was set as control. Injection of UOMVLs (1 mL, 0. 47 U/mL), UOX (1 mL, 0. 47 U/mL) and nothiy were given 1 h later in UOMVLs group (n=6), UOX group (n=6) and model group (n=6), and their serum uric acid levels were determined 1, 2, 3, 5, 7, 9, 12, 24, 36, 48 h after the establishment of hyperuricemia model. RESULTS: The entrapment efficiency of UOMVLs was (63. 75 ± 3. 65) %, with an average particle size of (22. 56 ± 1. 70) µm and Zeta potential of (-41. 81±6. 59) mV. The pharmacokinetic parameters of UOMVLs and UOX were as follows, respectively: area under time-concentration curve from 0 to infinity time (AUC0-∞) (498. 83 ± 58. 85) U/L . h and (28. 49 ± 9. 95) U/L . h; time to peak concentration (Tmax) (1. 00±0. 00) h and (0. 00±0. 00) h; peak concentration (Cmax) (73. 04±6. 35) U/L and (31. 00±6. 03) U/L; elimination half-life (t1/2) (3. 49±0. 80) h and (1. 17±0. 33) h. The relative bioavailability of UOMVLs was (1 750. 90±206. 56) %. UOMVLs decreased serum uric to normal in 9 h; whereas it took 48 h for the UOX group and the model group to return to normal. CONCLUSION: UOMVLs can prolong tmax and t1/2 and improve the relative bioavailability. UOMVLs decrease serum uric acid levels in rats with hyperuricemia more effectively than UOX.

[Correlation between in vitro release and in vivo absorption of sustained-releasing tablets of neostigmine bromide].

OBJECTIVE: To determine the correlation between in vitro release and in vivo absorption of sustained-releasing tablets of neostigmine bromide. METHODS: Water was used as dissolution medium to measured in vitro release of neostigmine bromide. After a single oral administration of 100 mg neostigmine bromide to rabbits, the plasma concentrations of neostigmine bromide in the rabbits were determined by HPLC. The compartment model and deconvolution method were employed to explain the in vitro-in vivo correlation. RESULTS: Using Y as cumulative in vitro release and Fa as percentage of absorption, the regression equation was established: Fa = 0.9298Y + 4.6074, r = 0.9961. The input function of R = 2.0163Y-11.242,r = 0.9270. CONCLUSION: The correlation between in vitro release and in vivo absorption of neostigmine bromide is good.

Improved biological properties and hypouricemic effects of uricase from Candida utilis loaded in novel alkaline enzymosomes.

OBJECTIVE: Previous studies on various enzymosomes (functional lipid vesicles encapsulating an enzyme) have been mostly carried out in vitro and have focused on preserving catalytic activity and improving the stability of the enzyme. Until now, few studies have focused on their in vivo fate. Similarly, although we have previously reported the increased in vitro uricolytic activity (about 2.2 times higher than that of free uricase, or three times higher than that of PEGylated uricase, Puricase(®), under physiological pH and temperature) and improved stability of the novel alkaline enzymosomes (functional lipid vesicles encapsulating uricase from Candida utilis: uricase-containing lipid vesicles, UOXLVs), it is still necessary to study the biological properties and hypouricemic effects of UOXLVs in vivo. METHODS: The enzyme kinetics, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary safety of UOXLVs were evaluated. RESULTS: The Michaelis constant (K(m)) value of the UOXLVs was slightly lower than that of the free enzyme. The enzyme release from the UOXLVs lasted over 12 hours and their circulation half-life was about sevenfold longer than that of the free uricase. Meanwhile, the UOXLVs had a 22-fold increase in the area under the curve compared with the free uricase. Furthermore, it took less than 3 hours for the UOXLVs to lower the plasma uric acid concentration from a high to a normal level, compared with 6 hours for the free uricase. In addition, the UOXLVs had much less immunogenicity than free uricase and were well tolerated by all animals throughout the observation period. CONCLUSION: The UOXLVs markedly improved the biological properties and enhanced the hypouricemic effects of uricase in vivo.

[Pharmacokinetics and relative bioavailability of neostigmine bromide sustained-release tablets].

OBJECTIVE: To study the pharmacokinetics and relative bioavailability of neostigmine bromide conventional tablets and sustained-release tablets in rabbits. METHODS: Six healthy rabbits were randomly divided into two groups for a cross self-contrast trial. RP-HPLC was used to detect plasma concentrations of neostigmine bromide. The pharmacokinetic parameters were calculated with the aid of DAS 2.0 software. RESULTS: The main pharmacokinetics parameters of the sustained-release tablets and conventional tablets were as follows, respectively: T(max)(3.67 +/- 1.51) hand (1.58 +/- 0.38) h; C(max) (5.04 +/- 1.19) mg/L and (4.56 +/- 1.70) mg/L; AUC(0 --> infinity) (32.82 +/- 9.88) mg/L x h and (29.84 +/- 14.27) mg/L x h. The relative bioavailability of the neostigmine bromide sustained-release tablets was 115.4%. CONCLUSION: The pharmacokinetics of neostigmine bromide accords with two compartments model, showing constant plasma concentration and relatively high bioavailability.