| Objective: To compare the pharmacokinetic and pharmacodynamic characteristics between rasagiline transdermal patchs and oral tablets and provide a theoretical basis for clinical rational use of drug.Methods:(1) Establish a high performance liquid chromatography-tandem mass spectrometric method(LC-MS/MS) for the quantification of rasagiline in human plasma. The separation was performed on the WATERS Xterra? RP18 colunm(4.6 mm × 100 mm, 3.5 μm) with the mobile phase consisted of acetonitrile and 20 mmoL·L-1 ammonium acetate containing 0.01% formic acid at a flow rate of 1 m L·min-1 under gradient elution. ESI source was applied and operated in multiple reaction monitoring(MRM) mode via positive ionization. Selegiline was used as the internal standard and the analysis was detected under the following condition: m/z 172.2→117.1 for rasagiline and m/z 188.2→119.2 for selegiline. Plasma samples were pretreated by acetonitrile precipitation.(2) Explore administration time and sample collection point of the experimental scheme about the pharmacokinetic and pharmacodynamic studies of rasagiline transdermal patchs. The trial design was random, open and parallel control. 6 healthy male subjects were randomly picked from volunteers and divided into two groups. A single transdermal patch delivering 1.25 mg rasagiline was applied to the two groups for 24 h and 48 h, respectively. Blood samples were collected before and after administration at different time to determine the concentration of rasagiline in plasma and the activity of MAO-B in platelet.(3) The comparative studies on pharmacokinetics between rasagiline transdermal patches and oral tablets on healthy subjects. The trial design was random, open and parallel control. 20 healthy male volunteers were separated to 2 groups randomly. The first group was administrated with a single dose of 1 mg rasagiline mesylate tablet. Meanwhile, single dose of 1.25 mg rasagiline transdermal patche was given to the other group. Before and after the administration, the blood samples were collected. The two groups proceeded with multiple-dose experiment 2 weeks later. Pharmacokinetic parameters were calculated with DAS 3.2.3 and analyzed using SPSS 17.0.(4) The comparative studies on pharmacodynamics between rasagiline transdermal patches and oral tablets on healthy subjects. During the time of pharmacokinetic studies, the blood samples, which were used to measure the activity of MAO-B in platelet, were also collected at different time before and after administration. The inhibition ratio of MAO-B activity, which was calculated based on the pre-administration activity, was regarded as the evaluation criteria of pharmacodynamics. Major pharmacodynamic parameters were estimated by DAS 3.2.3 and analyzed subsequently with SPSS 17.0.Results:(1) The method was proved to be sensitive, accurate, reproducible and suitable. Endogenous substances do not interfere with the detection of the internal standard and the analyte. A good linearity of rasagiline was obtained in the concentration range of 0.01~15 ng·m L-1 and the LLOQ was 0.01 ng·m L-1.(2) Groups of healthy volunteers were administrated with 1.25 mg rasagiline patches transdermally on shoulders for 24 h and 48 h, respectively. The experimental results indicated that there is no significant difference for the primary pharmacokinetic and pharmacodynamic parameters of rasagiline between different duration of administration with the same dose, thus transdermal administration of rasagiline patches for 48 h was selected in the subsequent clinical trials combining with the characteristics of drug release. In addition, the time for the last blood sampling for PK and PD were determined as 48 h and 312 h, respectively, according to the time which plasma concentration and platelet MAO-B activity returned to baseline level.(3) The results of pharmacokinetics between rasagiline transdermal patches and oral tablets showed that accumulations were found both after repeated administration of rasagiline mesylate tablets(dosing interval was 24 h) and rasagiline transdermal patches(dosing interval was 72 h), and the plasma concentration can reach the steady-state level. Compared to the tablets, rasagiline transdermal patches with a small degree of fluctuation presented relatively constant plasma concentration, prolonged half-life and significantly increased bioavailability.(4) The results of pharmacodynamics between rasagiline transdermal patches and oral tablets indicated that platelet MAO-B activity can achieved the steady-state level after multiple administration of rasagiline mesylate tablets for 5 times(dosing interval was 24h) and rasagiline patches for 3 times(dosing interval was 72h), and the MAO-B inhibition ratio after multiple administrations was significantly above single administration. At steady-state after repeated administration of 1mg oral tablets, the maximum inhibition was(90.4±4.7)%, plateau inhibition was(87.0±6.2)%, and effective inhibiton, which was defined as the inhibition rate higher than 80%, had been maintained for not less than 48 h. While the maxium inhibition of 1.25 mg patches was(94.3±2.5)%, plateau inhibition was(92.0±3.6)% and the duration of effective inhibition was 72 h. Compared to the tablets, rasagiline transdermal patches prolonged the time to the maximum of MAO-B inhibition ratio and presented more lasting inhibition, which laged behind the plasma concentration.Conclusion: Compared to the tablets, rasagiline transdermal patches presented relatively constant plasma concentration, more pharmacologically effectiveness and more durable inhibition of MAO-B. And this suggested us to reduce administration frequency and prolong dosing interval in clinical application in order to improve patient compliance. |
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