【摘要】 目的通过比较磷酸瑞格列汀片在不同程度肾功能不全患者与肾功能正常受试者的药代动力学差异,为制定肾功能不全患者的临床应用方案提供依据。方法32例受试者按肌酐清除率(Ccr)分入轻(60~89mL/min)、中(30~59mL/min)、重度肾功能不全(15~29mL/min)组、终末期肾病(<15mL/min)组及正常肾功能组,均单次口服磷酸瑞格列汀片50mg,采用液相色谱-质谱联用(LC-MS/MS)方法测定血浆及尿液中瑞格列汀(SP2086)及其代谢物瑞格列汀酸(SP2086酸)的浓度,采用WinNolin 6.1软件计算血浆药代动力学参数。结果轻、中、重度肾功能不全组、终末期肾病组以及正常肾功能组受试者服用瑞格列汀片后,SP2086分别在(1.07±0.35)、(1.50±0.89)、(1.67±2.16)、(2.42±2.15)和(1.75±1.21)h达到达峰浓度(Cmax),SP2086吸收入血后,迅速转化为主要活性代谢产物SP2086酸。轻度、中度、重度和终末期肾病组与正常肾功能组相比,SP2086和SP2086酸的Cmax和曲线下面积(AUC)逐渐增加;轻度、中度、重度和终末期肾病组SP2086和SP2086酸Tmax逐渐增加。轻、中、重度肾功能不全组、终末期肾病组以及正常肾功能组SP2086酸清除率(CL/F)分别为(23.50±6.01)、(12.90±4.34)、(6.71±1.55)、(3.06±0.48)和(30.50±10.70)L/h,SP2086酸0~96h Ae%分别为(71.7±14.3)%、(59.5±22.7)%、(63.3±13.9)%、(34.1±20.0)%和(74.2±14.6)%,CLR分别为(220.0±51.2)、(105.0±64.5)、(54.5±7.6)、(13.5±7.8)和(289.0±73.7)mL/min。各组SP2086 0~96h尿液累积排泄百分率(Ae%)平均为0.441%~4.530%。随着肾功能损害程度加重,SP2086和SP2086酸的CL/F明显递减,与正常肾功能组比,中度肾功能不全组的AUC0-∞为其1.44倍和2.32倍,重度肾功能不全组的AUC0-∞为其2.20倍和4.39倍,终末期肾病组的AUC0-∞为其2.83倍和9.28倍。结论正常肾功能患者磷酸瑞格列汀片的临床推荐剂量为100mg/d,本研究结果推荐轻度肾功能不全患者无需调整剂量;中度肾功能不全患者减至50mg/d;重度肾功能不全患者减至25mg/d;而终末期肾病患者不推荐使用磷酸瑞格列汀。更多还原

【Abstract】 Objective To compared the differences in pharmacokinetics of phosphate retagliptin tablets in patients with varying degrees of renal dysfunction.Methods A total of 32 patients were categorized into five groups according to their renal function:normal,mild dysfunction,moderate dysfunction,severe dysfunction,and end stage renal dysfunction(ESRD).All of the patients took a single dose of 50 mg phosphate retagliptin tablet.Their plasma and urinary concentrations of phosphate retagliptin(SP2086)and phosphate retagliptin acid(SP2086 acid)were determined using LC-MS/MS methods.The plasma pharmacokinetic parameters were calculated using WinNolin 6.1 software.Results Peak concentrations(Cmax)of SP2086 reached at(1.07±0.35)h in the patients with mild renal dysfunction,(1.50±0.89)h in the patients with moderate renal dysfunction,(1.67±2.16)h in the patients with severe renal dysfunction,(2.42±2.15)h in the patients with ESRD,and(1.75±1.21)h in the normal participants,with a clearance(CL/F)of(23.50±6.01),(12.90±4.34),(6.70±1.55),(3.10±0.48),and(30.50±10.70)L/h,respectively.With the increasing damages in renal function presented an incease in Cmax,time to reach Cmax(Tmax),and area under curve(AUC),a decrease in CL/F,of SP2086 and SP2086 acid.The 0-96 h urine cumulative excretion percentage(Ae%)of SP2086 ranged from 0.441% to 4.530%.The Ae% of SP2086 acid reached(71.7±14.3)% in the patients with mild renal dysfunction,(59.5±22.7)% in the patients with moderate renal dysfunction,(63.3±13.9)%in the patients with severe renal dysfunction,(34.1±20.0)%in the patient with ESRD,and(74.2±14.6)% in the normal participants,with a renal clearance(CLR)of(220.0±51.2),(105.0±64.5),(54.5±7.6),(13.5±7.8),and(289.0±73.7)mL/min,respectively.Compared with the participants with normal renal function,the AUCs of SP2086 and SP2086 acid were 1.44 times and 2.32 times higher in the patients with moderate renal dysfunction,2.20 times and 4.39 times higher in the patients with severe renal dysfunction,and 2.83 times and 9.28 times higher in the patients with ESRD.Conclusion The dosage of phosphate retagliptin tablet is recommended at 100 mg/d for patients with normal renal function and those with mild renal dysfunction,at 50 mg/d for patients with moderate renal dysfunction,and at 25 mg/d for patients with severe renal dysfunction.No phosphate retagliptin tablet is recommended for patients with ESRD.更多还原