格列本脲及其代谢产物在肾功能受损糖尿病患者中的药代动力学。
Pharmacokinetics of glibenclamide and its metabolites in diabetic patients with impaired renal function.
作者信息
Jönsson A, Rydberg T, Sterner G, Melander A
机构信息
Department of Internal Medicine, County Hospital Ryhov, Jönköping, Sweden.
出版信息
Eur J Clin Pharmacol. 1998 Feb;53(6):429-35. doi: 10.1007/s002280050403.
BACKGROUND
Glibenclamide (Gb) may provoke long-lasting hypoglycaemic reactions, and one of the known risk factors is impaired renal function. We have demonstrated Gb to have a terminal elimination half-life of 15 h, and the main metabolites have a hypoglycaemic effect. With few exceptions, detailed studies on second generation sulphonylureas in diabetics with impaired renal function are lacking. Therefore, we analysed the pharmacokinetics of Gb and its active metabolites, 4-trans-hydroxyglibenclamide (M1) and 3-cis-hydroxy-glibenclamide (M2) in this patient group.
METHODS
Two groups of 11 diabetic patients with impaired renal function (IRF, iohexol clearance range 7-42 ml.min(-1) . 1.73 m(-2)) or normal renal function (NRF, iohexol clearance range 75-140 ml.min(-1) . 1.73 m(-2)) were compared. A single oral 7-mg dose of Gb was administered after overnight fasting. Serum samples and urine collections were obtained over 48 h and 24 h, respectively. Concentrations of Gb, M1 and M2 were determined by a sensitive and selective high-performance liquid chromatography assay.
RESULTS
Peak serum values of M1 (24-85 ng.ml(-1) vs 16-57 ng.ml(-1)), M2 (7-22 ng.ml(-1) vs <5-18 ng.ml(-1)) and M1 + M2 (32-100 ng.ml(-1) vs 23-76 ng.ml(-1)) were higher in the IRF group. AUC and Cmax of Gb were lower and the clearance to bioavailability ratio (CL/f) was higher in the IRF group. AUC and Cmax of M1 were higher and CL/f lower in the IRF group. Much lower amounts of M and M2 were excreted in the urine in the IRF group (7.2% vs 26.4% in 24 h). The fraction of the Gb dose excreted as metabolites (fe(met) 0-24 h), ranged between 0.005 and 0.36 and correlated significantly with renal function measured by iohexol clearance. No other pharmacokinetic differences were found.
CONCLUSION
The differences in AUC, Cmax and CL/f of Gb may be explained by a higher free fraction in the IRF group which would increase Gb metabolic clearance. The inverse findings regarding M1 may be explained by the fact that the metabolites are primarily eliminated by the kidneys. After a single dose of Gb, neither Gb, M1 nor M2 seemed to accumulate in diabetic subjects with IRF. As only small amounts of M1 and M2 were excreted in the urine, this indicates one or several complementary non-renal elimination routes, e.g. shunting of metabolised Gb to the biliary excretion route and/or enterohepatic recycling of both metabolites and unmetabolised Gb.
背景
格列本脲（Gb）可能引发持久的低血糖反应，已知的风险因素之一是肾功能受损。我们已证明Gb的终末消除半衰期为15小时，且主要代谢产物具有降血糖作用。除少数例外情况外，缺乏对肾功能受损的糖尿病患者使用第二代磺酰脲类药物的详细研究。因此，我们分析了该患者群体中Gb及其活性代谢产物4-反式-羟基格列本脲（M1）和3-顺式-羟基格列本脲（M2）的药代动力学。
方法
比较两组各11例肾功能受损（IRF，碘海醇清除率范围为7 - 42 ml·min⁻¹·1.73 m⁻²）或肾功能正常（NRF，碘海醇清除率范围为75 - 140 ml·min⁻¹·1.73 m⁻²）的糖尿病患者。过夜禁食后单次口服7 mg剂量的Gb。分别在48小时和24小时内采集血清样本和尿液。通过灵敏且选择性的高效液相色谱法测定Gb、M1和M2的浓度。
结果
IRF组中M1的血清峰值（24 - 85 ng·ml⁻¹ 对比 16 - 57 ng·ml⁻¹）、M2的血清峰值（7 - 22 ng·ml⁻¹ 对比 <5 - 18 ng·ml⁻¹）以及M1 + M2的血清峰值（32 - 100 ng·ml⁻¹ 对比 23 - 76 ng·ml⁻¹）更高。IRF组中Gb的AUC和Cmax较低，清除率与生物利用度之比（CL/f）较高。IRF组中M1的AUC和Cmax较高，CL/f较低。IRF组中尿液中排出的M1和M2量要低得多（24小时内分别为7.2%对比26.4%）。以代谢产物形式排出的Gb剂量分数（fe(met) 0 - 24小时）在0.005至0.36之间，并且与通过碘海醇清除率测定的肾功能显著相关。未发现其他药代动力学差异。
结论
Gb的AUC、Cmax和CL/f的差异可能是由于IRF组中游离分数较高，这会增加Gb的代谢清除率。关于M1的相反发现可能是由于代谢产物主要通过肾脏消除这一事实。单次服用Gb后，Gb、M1和M2在肾功能受损的糖尿病患者中似乎均未蓄积。由于尿液中仅排出少量的M1和M2，这表明存在一条或几条互补的非肾脏消除途径，例如代谢后的Gb分流至胆汁排泄途径和/或代谢产物及未代谢的Gb的肠肝循环。
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