Tramadol Medicine In The Chinese Multi-ethnic Population Dynamic Studies

Objective: study is to establish a method concerning the analysis of tramadol and then to investigate PK of tramadol in healthy volunteers of different Chinese nationalities including Han. Mongolia. Korean, Hui and Uigur. In addition, we compare and analyze PK of tramadol in various nationalities and genders and examine the population pharmacokinetics of tramadol based on the concentration of five nationalities. Finally, the research would provide instruction and help for the usage of tramadol safely, reasonable and effectively to both clinic and remedy of battle wound.Methods: the assay for quantification of tramadol in plasma samples consisted of HPLC method with fluorescence detection as test facility, liquid-liquid extraction as extraction method, mobile phase including aqueous solution of sodium biphosphate (adjusted to pH 3.5 with orthophosphoric acid) - acetonitrile (77:23, V/V), 1.0 mL/min as flow rate and 275 nm and 302 nm as the excitation wave and emission wave respectively. The method concerning sample collection is as followed: a single oral dose of tramadol hydrochloride capsule (contain 100 mg tramadol) was given under fasting conditions to ten volunteers of each nationality (Both male and female have five volunteers respectively) and the time period of study is 36 h. Then, the research determinate the concentration of tramadol of Han, Mongolia, Korean, Muslim and Uigur volunteers through the established method above and acquire C_max and t_max directly from the data without calculation, AUC_0-t through calculation by using the linear trapezoidal rule, t_1/2 by the ratio of the 0.693 and k_e and other PK parameters through PK software DAS 2.0. Moreover, the ANOVA and Kruskal - Wallis rank test in the SPSS 11.5 were used as the method for the investigation of statistical significance of different nationalities and genders. Finally, the study of population pharmacokinetics was conducted with the help of nonlinear mixed-effect model (NONMEM).Result: Linearity of tramadol in the plasma was between 5 and 1000μg·L^-1; the within-day precision was lower than 4.6% (n=5) and between-day precision was lower than 7.7% (n=5). Besides, the method recovery is between 96.4% and 105.7% (n=5) and the recovery of tramadol plasma samples by liquid-liquid extraction ranged from 80.6% to 85.2% (n=5). Main PK parameters of Chinese Han are as followed: t_max is 2.40±0.74 h; C_max is 401.36±78μg·L^-1, t_1/2 is 6.24±1.03, V_d is 210.87±36.45 L, CL is 24.26±6.76 L·h^-1, AUC_0-36 is 4297.11±1261.08μg·h·L^-1, AUC_0-∞ is 4456.08±1318.81μg·h·L^-1. Main PK parameters of Chinese Mongolia are as followed: t_max is 1.95±0.35 h; C_max is 421.35±81.43μg·L^-1, t_1/2 is 6.30±1.20h, V_d is 203.58±31.71 L, CL is 23.23±6.15 L·h^-1, AUC_0-36 is 4465.32±1250.75μg·h·L^-1, AUC_0-∞ is 4646.58±1316.92μg·h·L^-1. Main PK parameters of Chinese Korean are as followed: t_max is2.00±0.87 h; C_max is 418.90±45.57μg·L^-1, t_1/2 is 6.15±1.59, V_d is 223.48±30.82 L, CL is 27.51±10.23 L·h^-1, AUC_0-36 is 3952.91±1322.02μg·h·L^-1, AUC_0-∞ is 4113.74±1466.23μg·h·L^-1. Main PK parameters of Chinese Hui are as followed: t_max is 2.55±0.69 h; C_max is 309.18±51.78μg·L^-1, t_1/2 is 6.75±0.96, V_d is 278.73±50.24 L, CL is 29.41±7.96 L·h^-1, AUC_0-36 is 3483.19±758.17μg·h·L^-1, AUC_0-∞ is 3612.95±818.19μg·h·L^-1. Main PK parameters of Chinese Uigur are as followed: t_max is 2.60±0.54 h; C_max is 350.56±43.54μg·L^-1, t_1/2 is 7.14±1.79,V_d is 251.69±69.40 L, CL is 25.56±8.17 L·h^-1, AUC_0-36 is 4111.64±1267.42μg·h·L^-1, AUC_0-∞ is 4368.51±1521.19μg·h·L^-1.Conclusion: the established method adapted to the assay of tramadol in the blood plasma. The results of five nationalities demonstrated significant individual difference after a single oral administration of tramadol hydrochloride. The results of statistics revealed there is no statistically different among the nationalities including Chinese Han, Chinese Mongolia, China Korean and Chinese Uigur. However, V_d, C_max of Chinese Hui showed a significant difference when compare with other nationalities. Kruskal-Wallis rank test manifested the disparities of t_max and t_1/2 among different nationalities and genders have no statistical significance.The regression equation of final model concerning the population pharmacokinetics of tramadol isCL =28.8×θ_1race×e^η₁ (L/h); V = 238×e^η₂ (L);Ka=1.84×θ_2rave×e^η₃ (/h).The PK performance in human body after a single oral administration were in accord with single compartment model and factors that influence the population pharmacokinetics of tramadol included the effect of nationality on CL and Ka.