Hernandez-Lopez C, Martinez-Farnos L, Karhu D, Perez-Campos T, Rovira S, Encina G
Clinical Research Department, ESTEVE, Mare de Deu de Montserrat, Barcelona, Spain.
Methods Find Exp Clin Pharmacol. 2006 Jul-Aug;28(6):373-8. doi: 10.1358/mf.2006.28.6.1007674.
The aim of this study was to compare the pharmacokinetic profile and oral bioavailability of Tramadol Contramid once-daily (o.d.) 200 mg tablets (Labopharm, Canada) with that of Zytram 200 mg tablets (Zambon, Spain), following single-dose administration in 26 healthy volunteers. The study had an open, randomized, crossover design with a 7-day wash-out. Data from 24 subjects were used for the pharmacokinetic (PK) analysis. Racemic tramadol and racemic O-demethyltramadol (M1) were assayed in plasma using a liquid chromatography/tandem mass spectrometry method. Primary PK parameters estimated were AUC(0-t), AUC(0-infinity), C(max), C(24 h), and T(max). Results were compared using an ANOVA, and the residual variability thereby obtained was used to construct the classical 90% confidence intervals. The parametric Schuirmann's test was also performed. T(max) was analyzed by a nonparametric approach. For both racemic tramadol and racemic O-demethyltramadol, the ANOVA showed a statistically significant formulation effect. Significantly higher values were obtained for Tramadol Contramid o.d. for all PK parameters, except for T(1/2). For Tramadol Contramid o.d., mean tramadol plasma levels were maintained at a plateau level above 200 ng/ml from 4 to 16 h after dose, while for the reference formulation, that level was sustained from 4 to only 6 h. Consistent results for both formulations were obtained for the metabolite. At the end of the dosing interval, plasma tramadol and O-demethyltramadol concentrations were 39% and 49% higher, respectively, for Tramadol Contramid o.d. than those for Zytram (p < 0.0001). Tramadol Contramid o.d. could be considered suprabioavailable to Zytram o.d.
本研究的目的是在26名健康志愿者单剂量给药后，比较曲马多控释片（加拿大Labopharm公司生产，每日一次，200mg片剂）与齐通（西班牙赞邦公司生产，200mg片剂）的药代动力学特征及口服生物利用度。本研究采用开放、随机、交叉设计，洗脱期为7天。24名受试者的数据用于药代动力学（PK）分析。采用液相色谱/串联质谱法测定血浆中的外消旋曲马多和外消旋O-去甲基曲马多（M1）。估算的主要PK参数为AUC(0-t)、AUC(0-∞)、C(max)、C(24 h)和T(max)。采用方差分析比较结果，并将由此获得的残余变异性用于构建经典的90%置信区间。还进行了参数Schuirmann检验。采用非参数方法分析T(max)。对于外消旋曲马多和外消旋O-去甲基曲马多，方差分析均显示出具有统计学意义的制剂效应。除T(1/2)外，曲马多控释片每日一次给药的所有PK参数值均显著更高。对于曲马多控释片每日一次给药，给药后4至16小时，曲马多血浆平均水平维持在200 ng/ml以上的平台期，而参比制剂的该水平仅在4至6小时维持。两种制剂的代谢产物结果一致。在给药间隔结束时，曲马多控释片每日一次给药的血浆曲马多和O-去甲基曲马多浓度分别比齐通高39%和49%（p < 0.0001）。曲马多控释片每日一次给药可被认为相对于齐通每日一次给药具有超生物利用度。
