达非那新缓释片在健康中国人体内的药动学

Pharmacokinetics of darifenacin extended-release tablets in healthy Chinese volunteers

目的建立达非那新血药浓度的液相色谱-质谱测定方法,研究其氢溴酸盐缓释片在人体内的药动学特征。方法血浆样本经碱化后用环己烷提取。流动相为甲醇-40mmol·L-1的醋酸铵水溶液(含0.05%甲酸)(52∶48,V/V);色谱柱采用Lichrospher C18(150mm×2.1mm,5μm)柱;采用气动辅助电喷雾离子化(ESI),正离子(positive)模式,选择性离子检测(SIM)。用DAS2.0软件计算药动学参数。结果该方法的浓度范围为0.03～20μg·L-1,最低定量限为0.03μg·L-1。10名健康受试者单次口服7.5、15、30mg3个剂量后的主要药动学参数ρmax分别为(1.8±s0.6)、(5.4±2.4)、(15±9)μg·L-1;AUC0～72分别为(33±12)、(100±18)、(203±71)μg·h·L-1;t1/2分别为(13±9)、(11±5)、(12±7)h。15mg多次给药后的稳态血药浓度ρssav为(6±4)μg·L-1。男、女各5名健康志愿受试者的药动学参数组间比较ρmax、tmax、t1/2、MRT、CL(F)、AUC0～72差异均无显著意义(均P>0.05)。结论达非那新在7.5～30mg剂量范围内呈非线性药动学特征,达非那新的药动学特征没有显著的性别差异。多剂量服药在人体内存在一定程度的蓄积。

AIM To establish a liquid chromatography-electrospray ionization mass spectrometry （LC- MS） method for the concentration determination and pharmacokinetics of darifenacin in healthy volunteers plasma. METHODS After being treated with saturated sodium bicarbonate, the plasma sample was extracted by cyclohexane and determined by LC-MS; and then was separated on a Lichrospher Cls （150 mm×2.1 mm, 5μm） column with a mobile phase of 40 mmol .L-1 ammonium containing 0.05% formic acid ： methanol （52 ： 48, V / V）. The selected ion monitoring with the positive mode was applied in the LC-MS. RESULTS The calibration curve was linear over the range of 0,03 - 20μg·L-1. The lower limit of quantification was 0.03 μg·L-1. After taking the three separated single oral administrations of darifenacin extended-release tablets 7.5 mg, 15 mg and 30 mg in 10 healthy volunteers, the main pharmacokinetic parameters were as follows： pmax （1.8 ±s 0.6）, （5.4 ±2.4） and （15 ± 9） Iμg·L-1, AUC0-72 （33 ± 12）, （100± 18） and （203 ±71） /xg-b.L-l, t1/2 （13±9） , （ 11 ±5） and （ 12 ± 7） h, respectively. After a multiple oral administration of darifenacin extended- release tablets 15 rag, the steady-state plasma concentration of the drug was （6 ±4） μg·L-1. No signifieant difference was shown in the pmax, t tl/2, MRT, CL （F）, AUC0-72 between the 5 male and 5 female volunteers. CONCLUSION The established method is rapid, simple and sensitive, showing a non-linear characteristic pharmacokinetics at three different single dose in healthy Chinese subjects. The increase rates of AUC and pmax of darifenacin were greater than those of the doses administered with no significant difference in the pharmacokinetic characterisitics between the male and female volunteers. An accumulation occurred after multiple administrations.