非洛地平与美托洛尔复方透皮贴剂的药代动力学和生物利用度评价

Evaluation of pharmacokinetics and bioavailability of felodipine and metoprolol transdermal patch

目的研究非洛地平(Fel)与美托洛尔(Met)复方透皮贴剂(Fel+Met-P)在兔体内的药代动力学和生物利用度。方法6只健康新西兰白兔分2次实验,先后分别随机交叉单次给予Fel+Met-P(1+10),(3+30)和(9+90)mg.kg-1,和随机交叉单次给予Fel+Met静脉注射液〔Fel+Met-I,(0.2+2)mg.kg-1〕、口服混悬液〔Fel+Met-S,(1+10)mg.kg-1〕及2药市售缓释片〔Fel+Met-T,(1+10)mg.kg-1〕,气相色谱-电子捕获法分别测定血浆中Fel和Met浓度,DAS软件计算药代动力学参数并进行生物利用度评价。结果Fel+Met-P血药浓度可平稳维持2～3d。在Fel+Met-P不同剂量组,Fel和Met的血药峰浓度(cmax)、血药-时曲线下面积(AUC)(0→60)和AUC(0→∞)分别随Fel+Met-P剂量增加而增大,且均与剂量(D)呈良好线性关系,Fel的回归方程为cmax=6.6342D+4.355(r=0.9969)和AUC(0→∞)=295.08D+92.322(r=0.9963),Met为cmax=8.4628D+51.528(r=0.9957)和AUC(0→∞)=315.14D+1474.8(r=0.9993);不同剂量组之间Fel和Met的达峰时间(tmax)、平均吸收时间(MAT)、平均驻留时间〔MRT(0→60)和MRT(0→∞)〕及各自绝对生物利用度均无显著性差异。与Fel+Met-S和Fel+Met-T比较,Fel+Met-P3个剂量组Fel和Met的tmax和MRT(0→∞)均延长,tmax分别为(21.5±8.1)～(27.0±12.3)和(25.3±14.4)～(37.5±10.0)h,MRT(0→∞)分别为(28.5±2.7)～(31.8±0.8)和(28.1±4.4)～(31.8±1.3)h;与Fel+Met-S比较,Fel的绝对生物利用度分别为Fel+Met-S的2.25,2.75和2.28倍,Met分别为Fel+Met-S的2.10,1.90和1.64倍;与Fel+Met-T比较,Fel的绝对生物利用度无明显变化,Met分别为Fel+Met-T的2.13,1.93和1.67倍。结论Fel+Met-P在兔体内具有缓释长效药代动力学特征,达到了提高药物生物利用度、延长药物体内驻留时间、维持平稳血药浓度和方便用药新剂型的设计目的。

AIM To study the pharmacokinetics and bioavailability of felodipine （ Fel ） and metoprolol （Met） transdermal patch （ Fel ＋ Met- P） in rabbits. METHODS The pharmacokinetics of Fel ＋ Met-P at 3 different doses [（ 1 ＋ 10） , （3 ＋30） and （9＋90） mg·kg^-1 and the bioavailabilities of Fel ＋ Met injection Fel ＋ Met-I, （ 0.2 ＋ 2 ） mg· kg^-1, suspension [Fel＋Met-S, （1 ＋10） mg· kg^-1 and controlled release tablets [ Fel ＋ Met-T, （ 1 ＋10） mg· kg^-1 were studied by using the randomized, 3-period and crossover experiment with 6 healthy New Zealand rabbits, respectively. Gas chromatography-electron capture detection assay was established for the quantity determination of Fel and Met in plasma at different time after drug administration. The pharmacokinetic parameters were calculated and statistical analysis wasperformed with DAS software. RESULTS The Fel and Met plasma concen-trations maintain steady for 2 -3 d after Fel ＋ Met-P was administered. Cmax, AUC（0→60）and AUC（0→∞） significantly increased with the elevation of Fel ＋ Met-P dose administered to rabbits, and the linear regressive equations for Fel were Cmax = 6. 6342D ＋ 4. 355 （ r = 0. 9969） and AUC（0→∞） = 295.08D ＋ 92. 322 （ r = 0. 9963 ）, and that for Met were Cmax = 8. 4628D ＋51. 528 （r = 0.9957） and AUC（0→∞）=315.14D ＋ 1474.8 （ r = 0. 9993 ）, the D in the equations is the dose of Fel or Met. But there were no significant differences in tmax, mean absorption time （ MAT ）, mean residence time （ MRT ） （0→60） MRT（0→∞） and absolute bioavailability among the 3 dose groups of Fel ＋ Met-P. The tmax and MRT of Fel ＋ Met-P were shown to be longer compared with that of Fel ＋ Met-S and Fel ＋ Met-T. The tmax of Fel and Met of the 3 doses of Fel ＋ Met-P was （21.5 ±8.1 ） - （27.0±12.3）h and （25.3 ±14.4） -（37.5 ± 10.0）h, and the MRT（0→∞） was （28.5 ±2.7） - （31.8 ±0.8）h and （28.1 ±4.4） - （31.8± 1.3） h, respectively. In the 3 dose groups of Fel ＋ Met-P, the absolute bioavailability of Fel increased 1.25, 1.75 and 1. 28 times, and that for Met increased 1.10, 0.90 and 0.64 times as against Fel ＋ Met-S, respectively. The absolute bioavailability of Fel had no changes compared with Fel ＋ Met-T, and that for Met increased 1.13, 0. 93 and 0. 67 times as against Fel ＋ Met-T, respectively. CONCLUSION Fel ＋ Met-P exhibits good controlled release properties and maintains relatively constant and sustained plasma concentrations of Fel and Met, which satisfies the demands of design for original new drug delivery system that enhances bioavailability and maintains appropriate blood levels of Fel and Met for a prolonged time without the adverse effects associated with frequent oral administration.