吗啉硝唑在中度肝功能减退者中的药动学  

Pharmacokinetics of morinidazole in patients with moderate hepatic impairment

作　　者：陈钊[1] 武晓捷[1] 张菁[1] 吴菊芳[1] 曹国英[1] 郁继诚[1] 施耀国[1] 张婴元[1] 

机构地区：[1]复旦大学附属华山医院抗生素研究所,卫生部抗生素临床药理重点实验室,上海200040

出　　处：《中国感染与化疗杂志》2013年第3期161-166,共6页Chinese Journal of Infection and Chemotherapy

基　　金：国家科技部"国家科技重大新药创制专项"资助(2012ZX09303004-001)

摘　　要：目的研究肝功能减退对吗啉硝唑及其代谢产物N-氧化代谢物(M2)人体药动学过程的影响,为制订吗啉硝唑在肝功能减退患者中的给药方案提供参考。方法采用平行开放对照试验设计,入选稳定的肝功能Child-Pugh B级患者12例为A组,根据A组患者的性别、年龄、体质量等特征匹配健康受试者作为平行对照的B组。A、B组受试者均单次静脉滴注500 mg吗啉硝唑氯化钠注射液后定时收集给药后0～48 h血样和分段尿样,采用高效液相色谱-串联质谱法(LC-MS/MS)检测血浆、尿液样本中的吗啉硝唑及M2浓度。结果 A组和B组受试者单剂静脉滴注吗啉硝唑500 mg后,平均药时曲线下面积(AUC0-∞)分别为116.3 mg.h/L和77.2 mg.h/L;消除半衰期(t1/2)分别为9.50 h和5.83 h;血浆药物总清除率(CLt)分别为4.75 L/h和7.23 L/h;肾清除率(CLr)分别为0.98 L/h和1.68 L/h。结果显示,与B组相比,A组吗啉硝唑在人体内药物暴露量(AUC)增加约68%,t1/2延长近3.7 h,CLt降低28%。A组和B组48 h内原药自尿中累积排出率分别为给药量的19.37%和22.93%。上述参数两组间差异均有统计学意义(P<0.01)。药动学参数变化主要原因是A组中3例受试者同时伴有轻度肾功能减退,此3例受试者的AUC较B组增加了124%(余9例肾功能正常者则增加了37%),并且药物的清除更慢,CLt为3.24 L/h,提示在肝功能减退同时伴肾功能减退时,对吗啉硝唑药动学有明显影响。两组中M2代谢比率均很低,分别为0.86%和1.25%。结论对于轻、中度肝功能减退患者,吗啉硝唑的给药方案可不作调整,但同时伴有肾功能减退患者,建议调整该药给药方案,其剂量的调整幅度需根据患者肾功能减退的程度而定。Objective To assess the effect of hepatic impairment on the pharmacokinetics of morinidazole and its metabolite M2 for proposing a clinical regimen of morinidazole in patients with hepatic impairment. Methods In a parallel-group, open-labled study, single dose of morinidazole was administered by intravenous infusion to the patients with stable moderate hepatic impairment according to the Child Pugh classification （category B） （group A, n = 12） and healthy controls （group B, n = 12） matched for gender, age and weight. Blood and urine samples for assay of morinidazole and its N-oxidative metabolite M2 were collected pre-dose and at frequent intervals up to 48 hours post-dose. Results After intravenous infusion of single dose of 500 mg morin idazole, mean values of AUC0-∞ were 116.3 mg · h/L in group A and 77.2 mg · h/L in group B. Mean values for t1/2 were 9.50 handS. 83 h, for CL, were 4.75 L/h and 7.23 L/h, for CLr were 0.98 L/h and 1.68 L/h. Compared with group B, morinidazole exposure in group A increased 68 %, elimination half-life prolonged about 3.7 hours and CL, decreased 28 %. The values of cumulative urine excretion rate of morinidazole were 19. 37% in group A and 22. 93% in group B. The metabolic rate of M2 was as low as 0. 86% in group A and 1.25% in group B. Three subjects in each group were found with mild renal impairment. Mean AUC0-∞ value for patients with hepatic and renal impairment was 124% higher than controis, but for patients with only hepatic impairment was 37% higher than controls. The slower drug elimination in patients with both moderate hepatic and renal impairment indicates that pharmacokinetics of morinidazole was affected indeed. Conclusions No dose or dosage adjustment of morinidazole may be required in patients with mild to moderate hepatic impairment. But for the patients with both hepatic and renal impairment, the dose adiustment may be required depending on renal function.

关 键 词：吗啉硝唑 中度肝功能减退 药动学 肾功能减退 给药方案 

分 类 号：R96[医药卫生—药理学]