磷酸二甲啡烷在中国健康人体的口服药代动力学（英文）
Pharmacokinetics of dimemorfan phosphate following single- and multiple-dose oral administration in healthy Chinese volunteers
-
摘要: 采用LC-MS/MS研究单次及多次口服给药后磷酸二甲啡烷在中国健康受试者体内药代动力学特征。单剂量试验的12例受试者采用两周期、交叉设计，分别口服本品10 mg、40 mg，以及其余12例受试者单次口服20 mg后的药代动力学参数:AUC0-48 h(11.81±14.46)、(52.60±96.01)、(34.70±29.59)ng·h/mL；t1/2(12.11±2.54)、(12.16±2.01)、(12.77±1.27)h；cmax(0.965 3±0.817 8)、(3.150±3.451)、(2.167±1.650)ng/mL。多剂量试验的12例受试者接受单剂量20 mg后，开始每天3次服用磷酸二甲啡烷20 mg，连服至第8天晨采集血样的药代动力学参数:AUC0-48 h(115.9±135.2)ng·h/mL；t1/2(11.22±1.61)h；cmax(7.418±7.010)ng/mL；累积常数Rcmax为(3.14±1.34)，RAUC为(3.38±1.22)。置信区间法表明磷酸二甲啡烷在10~40 mg范围内，药代动力学参数与剂量无线性关系；多次给药后在体内存在蓄积；磷酸二甲啡烷在中国健康受试者中存在显著的个体差异。Abstract: An LC-MS/MS method was developed to investigate the pharmacokinetic parameters in healthy Chinese volunteers following single and multiple oral administration of dimemorfan phosphate. A randomized, two-period and crossover study of 12 healthy volunteers was conducted with single-dose of 10 mg or 40 mg of dimemorfan phosphate. Another 12 volunteers were administered with 20 mg. The values of AUC0-48 h, t1/2, and cmax were(11. 81±14. 46), (52. 60±96. 01 )and(34. 70±29. 59)ng ·h/mL, (12. 11±2. 54), (12. 16±2. 01)and(12. 77±1. 27)h, and(0. 965 3±0. 817 8), (3. 150±3. 451)and(2. 167±1. 650)ng/mL for 10 mg, 40 mg and 20 mg oral administration. The same 12 healthy volunteers as the group of single-dose of 20 mg participated in multiple-dose study, who were administered with dimemorfan phosphate 20 mg, three-time a day until the day-8, AUC0-48 h, t1/2, and cmax were(115. 9±135. 2)ng ·h/mL, (11. 22±1. 61)h, and(7. 418±7. 010)ng/mL. The accumulation parameters Rcmax and RAUC were(3. 14±1. 34)and(3. 38±1. 22), respectively. Dose proportional of cmax and AUC was not concluded ranging from 10 mg to 40 mg after confidence interval criteria method. Accumulation occurred after multiple-dose administration. And the results demonstrated significant individual difference.
-
-
[1] Smith SM,Schroeder K,Fahey T.Over-the-counter(OTC)medications for acute cough in children and adults in ambulatory settings[J].Cochrane Database Syst Rev,2008, 8(2):142-143. [2] Kim JY,Kim HC,Kim J,et al.Concise synthesis of dimemorfan(DF)starting from 3-hydro-xymorphinan(3-HM)[J].Chem Pharm Bull(Tokyo),2008, 56(7):985-987. [3] Wang HH,Chou YC,Liao JF,et al.Dimemorfan enhances acetylcholine release from rat hippocampal slices[J].Brain Res,2004, 1008(1):113-115. [4] Shin EJ,Nah SY,Kim WK,et al.The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation:comparison with the effects of dextromethorphan[J].Brit J Pharmacol,2005, 144(7):908-918. [5] Shin EJ,Nabeshima T,Lee PH,et al.Dimemorfan prevents seizures induced by the L-type calcium channel activator BAY k-8644 in mice[J].Behav Brain Res,2004, 151(1/2):267-276. [6] Hasegawa C,Kumazaw T,Terada M,et al.A new method for quantitative determination of dimemorfan in human[J].Legal Med,2012, 14(5):267-271. [7] Tan HY,Peng JF,Pei Q,et al.Simple and sensitive LC-MS/MS-based assay for quantification of dimemorfan in human plasma for use in a pharmacokinetic study[J].Biomed Chromatogr,2014, 29(5):647-653. [8] Smith BP,Vandenhende FR,DeSante KA,et al.Confidence interval criteria for assessment of dose proportionality[J].Pharm Res,2000, 17(10):1278-1283. [9] Chou YC,Chung YT,Liu TY,et al.The oxidative metabolism of dimemorfan by human cytochrome P450 enzymes[J].J Pharm Sci,2010, 99(2):1063-1077. [10] Chou YC,Ueng YF,Chou CY,et al.Dimemorfan N-demethylation by mouse liver microsomal cytochrome P450 enzymes[J].Life Sci,2005, 77(7):735-745. [11] Pei Q,Peng JF,Tan HY,et al.Cytochrome P450 2D6*10 genotype affects the pharmacokinetics of dimemorfan in healthy Chinese subjects[J].Eur J Drug Metab Pharmacokinet,2015, 40(4):427-433. [12] Ida H.The nonnarcotic antitussive drug dimemorfan:a review[J].Clin Ther,1997, 19(12):215-231.
计量
- 文章访问数: 1167
- HTML全文浏览量: 5
- PDF下载量: 2188
下载:
