舒达吡啶与氯法齐明或克拉霉素联用增加脓肿分枝杆菌感染大鼠体内暴露水平的初步研究  

A preliminary study on the enhanced in vivo exposure of sudapyridine in Mycobacterium abscessus-infected rats with the co-administration of clofazimine or clarithromycin

作　　者：王雪钰 王宇津 初乃惠[1] 康万里[2] 聂文娟[1] Wang Xueyu;Wang Yujin;Chu Naihui;Kang Wanli;Nie Wenjuan(Department I of Tuberculosis,Beijing Chest Hospital,Capital Medical University,Beijing Tuberculosis and Thoracic Tumor Research Institute,Beijing 101149,China;Epidemiology Research Office,Beijing Chest Hospital,Capital Medical University,Beijing Tuberculosis and Thoracic Tumor Research Institute,Beijing 101149,China)

机构地区：[1]首都医科大学附属北京胸科医院(北京市结核病胸部肿瘤研究所)结核一科,北京101149 [2]首都医科大学附属北京胸科医院(北京市结核病胸部肿瘤研究所)流行病学研究室,北京101149

出　　处：《中国防痨杂志》2025年第2期150-157,共8页Chinese Journal of Antituberculosis

基　　金：国家自然科学基金(82100002)。

摘　　要：目的:研究舒达吡啶和贝达喹啉单用及分别与克拉霉素和氯法齐明联用在脓肿分枝杆菌感染大鼠模型中的体内药物分布情况和药物相互作用效果。方法:采用液相色谱-串联质谱法测定感染脓肿分枝杆菌的S-D大鼠模型在给予45 mg/kg舒达吡啶(A组)、45 mg/kg舒达吡啶+10 mg/kg克拉霉素(B组)和45 mg/kg舒达吡啶+25 mg/kg氯法齐明(C组)20 min、1 h和16 h后的血浆、大脑、椎骨和肺组织中舒达吡啶的浓度;同时测定给予40 mg/kg贝达喹啉(D组)、40 mg/kg贝达喹啉+10 mg/kg克拉霉素(E组)和40 mg/kg贝达喹啉+25 mg/kg氯法齐明(F组)1、4和16 h后的血浆、大脑、椎骨和肺组织中贝达喹啉的浓度。分析同一检测时间点同一部位不同组别药物浓度的差异情况。结果:对于舒达吡啶,在给药20 min后,B组的血浆药物浓度[390.6(319.6,621.9)ng/ml]高于A组[140.2(79.4,204.0)ng/ml];在给药1 h后,C组肺组织药物浓度[3478.1(2570.9,5322.7)ng/ml]低于A组[6632.0(5617.6,8014.1)ng/ml],差异均有统计学意义(U=0.000,P=0.004;U=4.000,P=0.025)。对于贝达喹啉,在给药4 h后F组的血浆药物浓度[2264.6(1724.4,3826.0)ng/ml]和给药16 h后的血浆、肺组织药物浓度[分别为2045.0(1922.8,3757.1)ng/ml、25095.3(13083.2,30438.4)ng/ml]均高于D组[分别为1415.3(671.9,1779.0)ng/ml、879.4(640.9,954.5)ng/ml、8671.0(4086.1,13530.3)ng/ml],差异均有统计学意义(U=3.000,P=0.016;U=0.000,P=0.004;U=2.000,P=0.010)。在用药16 h后,A组在血浆和肺组织的药物浓度[分别为2505.9(1844.7,2986.8)ng/ml和23481.4(16988.0,35219.7)ng/ml)]均明显高于D组[分别为879.4(640.9,954.5)ng/ml和8671.0(4086.1,13530.3)ng/ml],差异均有统计学意义(U=5.000,P=0.037;U=2.000,P=0.010)。结论:与单用药相比,舒达吡啶与克拉霉素联用可能增加其在体内的暴露水平,且在给药16 h后在血浆和肺组织的暴露水平均优于贝达喹啉,可为组成抗MAB治疗方案提供理论依据。Objective:To investigate the in vivo drug distribution and drug interaction effects of sudapyridine and bedaquiline as monotherapy and in combination with clarithromycin and clofazimine in a rat model infected with Mycobacterium abscesses.Methods:Liquid chromatography-tandem mass spectrometry was employed to determine the concentrations of sudapyridine in plasma,brain,vertebrae,and lung tissues of S-D rats infected with Mycobacterium abscessus at 20 min,1 hour,and 16 hours after administration of 45 mg/kg sudapyridine(group A),45 mg/kg sudapyridine+10 mg/kg clarithromycin(group B),and 45 mg/kg sudapyridine+25 mg/kg clofazimine(group C).Similarly,the concentrations of bedaquiline were measured in plasma,brain,vertebrae,and lung tissues at 1,4,and 16 hours after administration of 40 mg/kg bedaquiline(group D),40 mg/kg bedaquiline+10 mg/kg clarithromycin(group E),and 40 mg/kg bedaquiline+25 mg/kg clofazimine(group F).The differences in drug concentrations at the same detection time points and in the same tissue among different groups were analyzed.Results:For sudapyridine,at 20 minutes post-administration,the plasma drug concentration in group B(390.6(319.6,621.9)ng/ml)was higher than that in group A(140.2(79.4,204.0)ng/ml);at 1 hour post-administration,the lung tissue drug concentration in group C(3478.1(2570.9,5322.7)ng/ml)was lower than that in group A(6632.0(5617.6,8014.1)ng/ml),with both differences being statistically significant(U=0.000,P=0.004;U=4.000,P=0.025).For bedaquiline,at 4 hours post-administration,the plasma drug concentration in group F(2264.6(1724.4,3826.0)ng/ml)and at 16 hours post-administration,the plasma and lung tissue drug concentrations(2045.0(1922.8,3757.1)ng/ml and 25095.3(13083.2,30438.4)ng/ml)were all higher than those in group D(1415.3(671.9,1779.0)ng/ml,879.4(640.9,954.5)ng/ml,8671.0(4086.1,13530.3)ng/ml),with all differences being statistically significant(U=3.000,P=0.016;U=0.000,P=0.004;U=2.000,P=0.010).At 16 hours after administration,the drug concentrations in plasma and lung tiss

关 键 词：临床前药物评价 药物协同作用 药物监测 组织分布 克拉霉素 舒达吡啶 

分 类 号：R52[医药卫生—内科学] R969.1[医药卫生—临床医学] R978.3