单次用硝酸异山梨酯透皮贴剂在健康志愿者的药代动力学

Pharmacokinetics of isosorbide dinitrate and momonitrate metabolites in healthy volunteers following application of isosorbide dinitrate transdermal therapeutic system

目的研究健康受试者单次用硝酸异山梨酯透皮贴剂(抗心绞痛药)的药代动力学及安全性。方法28名健康志愿者随机分为3个剂量组,分别单次用硝酸异山梨酯透皮贴剂40、80和120 mg,用HPLC-GC测定血浆硝酸异山梨酯及代谢物2-单硝基异山梨酯和5-单硝基异山梨酯的浓度,用Wi nNonLi n 5.0计算其主要药代动力学参数。密切观察不良事件。结果3个剂量组分别单次用不同剂量的硝酸异山梨酯透皮贴剂后的主要药代动力学参数,硝酸异山梨酯:Cmax分别为(4.56±0.64)、(7.85±1.59)和(12.75±2.57)ng.mL-1;AUC0-tn分别为(301.14±52.93)、(530.83±124.51)和(790.33±201.10)ng.mL-1.h。2-单硝基异山梨酯:Cmax分别为(4.00±0.49)、(6.72±0.97)和(10.45±1.74)ng.mL-1;AUC0-tn分别为(250.89±33.78)、(435.21±85.14)和(625.93±140.44)ng.mL-1.h。5-单硝基异山梨酯:Cmax分别为(10.57±1.17)、(20.35±1.54)和(30.31±4.58)ng.mL-1;AUC0-tn分别为(661.783±80.773)、(1335.46±164.85)和(1905.14±330.69)ng.mL-1.h。本试验共发生10件与研究药有关的不良事件,主要为转氨酶一过性升高(7.1%)、头痛(21.4%)和贴皮处瘙痒(7.1%)。结论在40～120 mg内,硝酸异山梨酯的体内过程呈线性药代动力学特征。

Objective To study the pharmacokinetics and safety in healthy volunteers following application of isosorbide dinitrate （ID） trans- dermal therapeutic system （ IDTTS ）. Methods Twenty-eight healthy volunteers were randomized to administer a single dose of isosorbide dinitrate transdermal therapeutic system at 40 mg,80 mg and 120 mg , respectively. The concentration of isosorbide dinitrate （ID） and momonitrate metabolites （2-IDM and 5-IDM） in human plasma were determined by HPLC-GC. The main pharmacokinetic parameters were calculated with WinNonLin 5.0. Adverse event was nearly observed. Results The main pharmacokinetic parameters of ID after single doses of 40 mg,80 mg and 120 mg were as follows： Cmax, were （4.56 ±0. 64）, （7.85 ± 1.59） and（12.75 ±2.57） ng.mL^-1; AUC0-tn were （301.14 ±52.93）, （530. 83 ± 124.51 ） and（790. 33 ± 201.10） ng.mL^-1.h , respectively. The main pharmacokinetic parameters of 2-ISMN were as follows：Cmax were （4. 00±0. 49 ）, （ 6. 72 ±0. 97 ） and （ 10. 45 ± 1.74） ng.mL^-1 ; AUC0-t, were （ 250. 89 ± 33.78 ）, （ 435.21 ± 85.14）and（625.93 ± 140. 44）ng.mL^-1.h, respectively. The main pharmacokinetic parameters of 5-ISMN were as follows ： Cmax were （4. 00 ± 0. 49）, （ 6. 72 ± 0. 97 ） and （ 10. 45 ± 1.74 ） ng .mL^-1 ; AUC0-tn were （ 250. 89 ± 33.78 ）, （435.21 ± 85.14）and （625.93±140. 44）ng.mL^-1.h, respectively. Ten events were judged by the investigator to be related to study drug, including hepatic enzymes in creased （7. 1% ）, headache （21.4%）, pruritus of the area around the patch （7.1%）, respectively. Conclusion The process of IDTTS in the dosage range of 40 - 120 mg fit linear dynamic feature.