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The safety and pharmacokinetics of metformin in patients with chronic liver disease.
Alimentary Pharmacology & Therapeutics ( IF 6.6 ) Pub Date : 2020-01-21 , DOI: 10.1111/apt.15635
Felicity C Smith 1, 2 , Sophie L Stocker 1, 3 , Mark Danta 3, 4 , Jane E Carland 1, 3 , Shaun S Kumar 1 , Zhixin Liu 5 , Jerry R Greenfield 3, 6, 7 , Hannah E Braithwaite 1 , Tim S Cheng 1 , Garry G Graham 1, 2 , Kenneth M Williams 1, 2 , Richard O Day 1, 2, 3
Affiliation  

BACKGROUND The FDA approved 'label' for metformin lists hepatic insufficiency as a risk for lactic acidosis. Little evidence supports this warning. AIMS To investigate the safety and pharmacokinetics of metformin in patients with chronic liver disease (CLD). METHODS Chronic liver disease patients with and without type 2 diabetes mellitus (T2DM) were studied by a cross-sectional survey of patients already prescribed metformin (n = 34), and by a prospective study where metformin (500 mg, immediate release, twice daily) for up to 6 weeks was prescribed (n = 24). Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were obtained and compared to previously published values from healthy and T2DM populations without CLD. RESULTS All plasma metformin and lactate concentrations remained below the putative safety thresholds (metformin, 5 mg/L; lactate, 5 mmol/L). Lactate concentrations were unrelated to average steady-state metformin concentrations. In patients with CLD, T2DM was associated with higher plasma lactate concentrations (48% higher than those without T2DM, P < 0.0001). CLD patients with cirrhosis had 23% higher lactate concentrations than those without cirrhosis (P = 0.01). The pharmacokinetics of metformin in CLD patients were similar to patients with T2DM and no liver disease. The ratio of apparent metformin clearance (CLMet /F) to creatinine clearance was marginally lower in CLD patients compared to healthy subjects (median, interquartile range; 12.6, 9.5-15.9 vs 14.9, 13.4-16.4; P = 0.03). CONCLUSIONS The pharmacokinetics of metformin are not altered sufficiently in CLD patients to raise concerns regarding unsafe concentrations of metformin. There were no unsafe plasma lactate concentrations observed in CLD patients receiving metformin (ACTRN12619001292167; ACTRN12619001348145).

中文翻译:

二甲双胍在慢性肝病患者中的安全性和药代动力学。

背景技术FDA批准的二甲双胍“标签”将肝功能不全列为乳酸性酸中毒的风险。几乎没有证据支持该警告。目的探讨二甲双胍在慢性肝病(CLD)患者中的安全性和药代动力学。方法通过对已经开具二甲双胍(n = 34)的患者进行横断面调查以及一项前瞻性研究,对二甲双胍(500 mg,立即释放,每天两次)进行回顾性研究,研究有无2型糖尿病(T2DM)的慢性肝病患者。 ),最多可开6周(n = 24)。监测血浆二甲双胍和乳酸浓度。从没有CLD的健康人群和T2DM人群中获得了单独的药代动力学并将其与以前发表的值进行了比较。结果所有血浆二甲双胍和乳酸浓度均低于假定的安全性阈值(二甲双胍为5 mg / L;乳酸为5 mmol / L)。乳酸浓度与稳态二甲双胍平均浓度无关。在患有CLD的患者中,T2DM与血浆乳酸浓度更高(比不使用T2DM的患者高48%,P <0.0001)。患有肝硬化的CLD患者的乳酸浓度比没有肝硬化的CLD患者高23%(P = 0.01)。二甲双胍在CLD患者中的药代动力学与T2DM无肝病的患者相似。与健康受试者相比,CLD患者的表观二甲双胍清除率(CLMet / F)与肌酐清除率的比率略低(中位数,四分位数范围; 12.6、9.5-15.9与14.9、13.4-16.4; P = 0.03)。结论在CLD患者中,二甲双胍的药代动力学变化不充分,引起对二甲双胍浓度不安全的担忧。在接受二甲双胍的CLD患者中未观察到不安全的血浆乳酸浓度(ACTRN12619001292167; ACTRN12619001348145)。
更新日期:2020-01-22
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