食物与性别对米格列奈钙人体内药物动力学的影响
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摘要
一、目的
建立一种可靠、高效、简便的UPLC-MS/MS方法,测定米格列奈在人血浆中的浓度,考察米格列奈钙片在健康受试者体内的药物动力学特性。
24名健康受试者分别在空腹和餐状态下给予米格列奈钙片剂,考察食物及性别对单次递增剂量的米格列奈钙片药动学的影响。
二、方法
1.1测定方法
血浆样品以乙腈蛋白沉淀法处理,以那格列奈为内标,采用UPLC-MS/MS法测定血浆中米格列奈的浓度。
1.2给药方法
采用随机,单次给药(3个剂量组),双周期交叉自身对照的设计,24名健康志愿受试者第一周期分别在禁食一夜(空腹)或低脂早餐后(餐后)单次口服5、10、20 mg的米格列奈钙；经7天的洗脱期后,第二周期志愿者在餐后或空腹状态下给予同样剂量的药物。
1.3生物样本采集
米格列奈钙血样分别于试验当天早晨米格列奈钙服药前0小时(h)及服药后5,10,15,20,30,45分钟(min)和1,1.5,2,3,4,6,8 h取静脉血4 mL。置肝素试管中,离心分离出血浆,置-70℃冰箱中保存至测定。
1.4不良反应监测
受试者服用米格列奈钙后,于2和6 h分别监测血压,心率,心电图,记录各项不良反应。
三、结果
1.米格列奈的测定
米格列奈在10.0～7000.0ng/mL浓度范围内线性关系良好,最低检测浓度为10.0 ng/mL。萃取回收率均在89.06%～99.81%之间,方法回收率在86.00%～112.00%之间,日内、日间RSD均不高于12.49%,低,中,高三种浓度的质控样品稳定性良好,变异均不高于10.51%。
2.食物对米格列奈钙药动学的影响
24名健康志愿者,分为3组,每组8人[男女各半]。受试者单次空腹和餐后口服米格列奈钙后,与空腹组相比较,餐后服用米格列奈钙使Cmax减小了60.4%-65.2%(5 mg：60.4%,10 mg：64.9%,20 mg：65.2%)；餐后服用米格列奈使Tmax延长了0.88-1.68 h(5 mg：1.75 h vs0.36 h；10 mg：1.97 h vs 0.29 h和20mg：1.18 h vs 0.30 h)；餐后和空腹状态的AUCs值相似；食物不影响米格列奈钙的体内消除。
3.性别对米格列奈钙药动学的影响
无论受试者是空腹状态还是餐后状态服用米格列奈钙,同一剂量组受试者两个周期、餐后和空腹的平均药动学参数值均无统计学差异(P>0.05)。因此,性别不影响米格列奈钙的药动学参数。
4.不良事件
米格列奈钙片剂耐受性良好,整个试验过程中,未见任何与药物相关的严重不良事件的发生。
四、结论
1.方法学
本研究建立的UPLC-MS/MS具有较好的灵敏度及专属性,样品处理简单,大大缩短了分析测定时间。在实际应用中,此方法能够满足米格列奈钙的临床药物动力学的研究。
2.药动学
本文报道了食物与性别对米格列奈钙在中国健康人体内的药动学的影响。在整个试验中,食物影响5 mg,10 mg和20 mg的米格列奈钙在健康受试者体内的口服吸收速度,不影响三个剂量组药物在受试者体内的吸收程度,但无论是健康受试者空腹或餐后口服米格列奈钙,性别均不影响其药动学参数。
3.安全性
整个试验过程受试者对三个剂量组药物均能很好的耐受。
OBJECTIVES
To establish a reliable, efficient and simple ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method for the determination of mitiglinide (MGN) in human plasma; The volunteers received the same dose under the fed or fasted condition, to assess the effects of food and gender on the pharmacokinetic (PK) properties of MGN calcium tablets.
METHODS
1.1 Determination of MGN in human plasma
Plasma sample preparation was performed by using protein precipitation. Nateglinide used as the internal standard (IS). Concentrations of MGN in plasma were determined using UPLC-MS/MS.
1.2 Dose administration
In this open-label, randomized, single-dose (3 distinct doses),2-way crossover PK study, three doses of MGN calcium 5,10 or 20 mg were administered to healthy adult volunteers after an overnight fast (fasted condition) or low-fat breakfast (fed condition) (period 1). After 7 days, the participants received the same dose under the opposite fed/fasted condition (period 2).
1.3 Biology samples collection
Serial blood samples were collected from an in-dwelling venous catheter (anticoagulated with sodium heparin) at 5,10,15,20,30,45 min and 1,1.5,2,3,4,6,8h before and after MGN calcium administration. Blood samples were collected in plastic containers, and immediately centrifuged. The separated plasma samples were immediately frozen at-70℃until assayed.
1.4 Safety monitoring
Adverse event was elicited from the volunteers by means of spontaneous report and specific questioning. Serial measurements of blood pressure, heart rate, and ECG were recorded 2 and 6 h after MGN administration.
RESULTS
1. Determination of MGN
The standard calibration curve was linear (range,10.0-7000.0 ng/mL) for MGN (r2=0.999 8, n=7). The lower limit of quantification (LLOQ) was 10.0 ng/mL. The extraction recovery and methodology recovery ranged from 89.06% to 99.81%, and 86.00% to 112.00%, respectively. The intraday and interday relative standard deviation (RSD) were≤12.49%. The stability tests showed that the plasma samples of MGN were all stable under different conditions(RSD≤8.14%).
2. The effects of food on the PK of MGN calcium
A total of twenty-four Chinese volunteers 8 [4 men,4 women] volunteers per group were enrolled in the study. Food reduced the Cmax of rapidly absorbed MGN calcium by 60.4% to 65.2%(5 mg:60.4%,10 mg: 64.9%,20 mg:65.2%). The mean Tmax was significantly delayed form 0.88h to 1.68 h by the presence of food compared with fasting conditions (5mg:1.75h vs 0.36h; 10mg:1.97h vs 0.29h and 20mg:1.18h vs 0.30 h). However, the extent of MGN calcium absorption did not appear to change as evidenced by similar AUCs for fasted and fed conditions.
3. The effects of gender on the PK of MGN calcium
There were no significant gender differences found in the PK properties of MGN in either fasted or fed states in the some dose group (P>0.05). Gender did not appear to affect the PK properties of MGN calcium.
3. Adverse events assessment
The drug was well tolerated, and no drug-related serious adverse events were reported in the whole test.
CONCLUSIONS
1. Methods
The UPLC-MS/MS method that was developed for this study used a simple technique for sample preparation and was associated with good sensitivity, reproducibility, and specificity. It can be used for the PK study of MGN calcium.
2. PK test
We reported the effects of food and gender on the PK profile of MGN calcium tablets after single oral administration in healthy adults. In this PK study, food intake did not appear to affect the extent of absorption (ie, total exposure) of single doses of MGN calcium 5 mg,10 mg and 20 mg in these healthy adult volunteers. But it affected the absorption rate of oral MGN calcium at all the three doses. Gender did not appear to affect the PK properties of MGN calcium in both states.
3. Safety test
The three single doses appeared to be well tolerated.
建立一种可靠、高效、简便的UPLC-MS/MS方法,测定米格列奈在人血浆中的浓度,考察米格列奈钙片在健康受试者体内的药物动力学特性。
24名健康受试者分别在空腹和餐状态下给予米格列奈钙片剂,考察食物及性别对单次递增剂量的米格列奈钙片药动学的影响。
二、方法
1.1测定方法
血浆样品以乙腈蛋白沉淀法处理,以那格列奈为内标,采用UPLC-MS/MS法测定血浆中米格列奈的浓度。
1.2给药方法
采用随机,单次给药(3个剂量组),双周期交叉自身对照的设计,24名健康志愿受试者第一周期分别在禁食一夜(空腹)或低脂早餐后(餐后)单次口服5、10、20 mg的米格列奈钙；经7天的洗脱期后,第二周期志愿者在餐后或空腹状态下给予同样剂量的药物。
1.3生物样本采集
米格列奈钙血样分别于试验当天早晨米格列奈钙服药前0小时(h)及服药后5,10,15,20,30,45分钟(min)和1,1.5,2,3,4,6,8 h取静脉血4 mL。置肝素试管中,离心分离出血浆,置-70℃冰箱中保存至测定。
1.4不良反应监测
受试者服用米格列奈钙后,于2和6 h分别监测血压,心率,心电图,记录各项不良反应。
三、结果
1.米格列奈的测定
米格列奈在10.0～7000.0ng/mL浓度范围内线性关系良好,最低检测浓度为10.0 ng/mL。萃取回收率均在89.06%～99.81%之间,方法回收率在86.00%～112.00%之间,日内、日间RSD均不高于12.49%,低,中,高三种浓度的质控样品稳定性良好,变异均不高于10.51%。
2.食物对米格列奈钙药动学的影响
24名健康志愿者,分为3组,每组8人[男女各半]。受试者单次空腹和餐后口服米格列奈钙后,与空腹组相比较,餐后服用米格列奈钙使Cmax减小了60.4%-65.2%(5 mg：60.4%,10 mg：64.9%,20 mg：65.2%)；餐后服用米格列奈使Tmax延长了0.88-1.68 h(5 mg：1.75 h vs0.36 h；10 mg：1.97 h vs 0.29 h和20mg：1.18 h vs 0.30 h)；餐后和空腹状态的AUCs值相似；食物不影响米格列奈钙的体内消除。
3.性别对米格列奈钙药动学的影响
无论受试者是空腹状态还是餐后状态服用米格列奈钙,同一剂量组受试者两个周期、餐后和空腹的平均药动学参数值均无统计学差异(P>0.05)。因此,性别不影响米格列奈钙的药动学参数。
4.不良事件
米格列奈钙片剂耐受性良好,整个试验过程中,未见任何与药物相关的严重不良事件的发生。
四、结论
1.方法学
本研究建立的UPLC-MS/MS具有较好的灵敏度及专属性,样品处理简单,大大缩短了分析测定时间。在实际应用中,此方法能够满足米格列奈钙的临床药物动力学的研究。
2.药动学
本文报道了食物与性别对米格列奈钙在中国健康人体内的药动学的影响。在整个试验中,食物影响5 mg,10 mg和20 mg的米格列奈钙在健康受试者体内的口服吸收速度,不影响三个剂量组药物在受试者体内的吸收程度,但无论是健康受试者空腹或餐后口服米格列奈钙,性别均不影响其药动学参数。
3.安全性
整个试验过程受试者对三个剂量组药物均能很好的耐受。
OBJECTIVES
To establish a reliable, efficient and simple ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method for the determination of mitiglinide (MGN) in human plasma; The volunteers received the same dose under the fed or fasted condition, to assess the effects of food and gender on the pharmacokinetic (PK) properties of MGN calcium tablets.
METHODS
1.1 Determination of MGN in human plasma
Plasma sample preparation was performed by using protein precipitation. Nateglinide used as the internal standard (IS). Concentrations of MGN in plasma were determined using UPLC-MS/MS.
1.2 Dose administration
In this open-label, randomized, single-dose (3 distinct doses),2-way crossover PK study, three doses of MGN calcium 5,10 or 20 mg were administered to healthy adult volunteers after an overnight fast (fasted condition) or low-fat breakfast (fed condition) (period 1). After 7 days, the participants received the same dose under the opposite fed/fasted condition (period 2).
1.3 Biology samples collection
Serial blood samples were collected from an in-dwelling venous catheter (anticoagulated with sodium heparin) at 5,10,15,20,30,45 min and 1,1.5,2,3,4,6,8h before and after MGN calcium administration. Blood samples were collected in plastic containers, and immediately centrifuged. The separated plasma samples were immediately frozen at-70℃until assayed.
1.4 Safety monitoring
Adverse event was elicited from the volunteers by means of spontaneous report and specific questioning. Serial measurements of blood pressure, heart rate, and ECG were recorded 2 and 6 h after MGN administration.
RESULTS
1. Determination of MGN
The standard calibration curve was linear (range,10.0-7000.0 ng/mL) for MGN (r2=0.999 8, n=7). The lower limit of quantification (LLOQ) was 10.0 ng/mL. The extraction recovery and methodology recovery ranged from 89.06% to 99.81%, and 86.00% to 112.00%, respectively. The intraday and interday relative standard deviation (RSD) were≤12.49%. The stability tests showed that the plasma samples of MGN were all stable under different conditions(RSD≤8.14%).
2. The effects of food on the PK of MGN calcium
A total of twenty-four Chinese volunteers 8 [4 men,4 women] volunteers per group were enrolled in the study. Food reduced the Cmax of rapidly absorbed MGN calcium by 60.4% to 65.2%(5 mg:60.4%,10 mg: 64.9%,20 mg:65.2%). The mean Tmax was significantly delayed form 0.88h to 1.68 h by the presence of food compared with fasting conditions (5mg:1.75h vs 0.36h; 10mg:1.97h vs 0.29h and 20mg:1.18h vs 0.30 h). However, the extent of MGN calcium absorption did not appear to change as evidenced by similar AUCs for fasted and fed conditions.
3. The effects of gender on the PK of MGN calcium
There were no significant gender differences found in the PK properties of MGN in either fasted or fed states in the some dose group (P>0.05). Gender did not appear to affect the PK properties of MGN calcium.
3. Adverse events assessment
The drug was well tolerated, and no drug-related serious adverse events were reported in the whole test.
CONCLUSIONS
1. Methods
The UPLC-MS/MS method that was developed for this study used a simple technique for sample preparation and was associated with good sensitivity, reproducibility, and specificity. It can be used for the PK study of MGN calcium.
2. PK test
We reported the effects of food and gender on the PK profile of MGN calcium tablets after single oral administration in healthy adults. In this PK study, food intake did not appear to affect the extent of absorption (ie, total exposure) of single doses of MGN calcium 5 mg,10 mg and 20 mg in these healthy adult volunteers. But it affected the absorption rate of oral MGN calcium at all the three doses. Gender did not appear to affect the PK properties of MGN calcium in both states.
3. Safety test
The three single doses appeared to be well tolerated.
引文
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[1]Groop LC, Widen E, Ferrannini E. Insulin resistance and insulin deficiency in the pathogenesis of type 2 (non-insulin-dependent) diabetes mellitus:Errors of metabolism or of methods? Diabetologia.1993,36:1326-1331.
[2]Ward WK, Bolgiano DC, McKnight B, et al. Diminished β cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Chin Invest.1984,74(4): 1318-1328.
[3]DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care.1992,15(3):318-368.
[4]Kelley D, Mokan M, Veneman T. Impaired postprandial glucose utilization in noninsulin-dependent diabetes mellitus. Metabolism.1994,43(12):1549-1557.
[5]Firth RG, Bell PM, Marsh HM, et al. Postprandial hyperglycemia in patients with noninsulin-dependent diabetes mellitus. Role of hepatic and extrahepatic tissues. J Chin Invest.1986,77(5):1525-1532.
[6]Asplund K, Wiholm BE, Lithner F. Glibenclamide-associated hypoglycaemia:A report on 57 cases. Diabetologia.1983,24(6):412-417.
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[11]Ohnotal H, Kitamura T, Kinukawa M, et al. A Rapid-and Short-Acting Hypoglycemic Agent KAD-1229 Improves Post-Prandial Hyperglycemia and Diabetic Complication in Streptozotocin-Induced Non-Insulin-Dependent Diabetes Mellitus Rats. Jpn. J. Pharmacol.1996,71:315-323.
[12]Tahara A, Yokono AM, Shibasaki M. Effects of antidiabetic drugs in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice.Eur J Pharmacol.2011, 655:108-116.
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[14]Ohnota H, Koizumi T, Tsutsumi N, et al. Novel rapid- and short-acting hypoglycemic agent, a calcium(2s)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate (KAD-1229) that acts on the sulfonylurea receptor:comparison of effects between KAD-1229 and gliclazide.J Pharmacol Exp Ther.1994,269(2):489-495.
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[18]汪志娟,李见春,董海军,等.米格列奈钙片单、多次给药人体药代动力学研究.安徽医药杂志,2009,13(9)：1028-1031.
[19]Yu L, Lu S, Lin Y, et al. Carboxyl-glucuronidation of mitiglinide by human UDP-glueuronosyltransferases[J]. Biochem Pharmacol,2007,73(11):1842-1851.
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[21]王广宇,朱旅云,马利成,等.米格列奈治疗2型糖尿病临床试验研究.临床内科杂志,2006,23(12)：812-814.
[22]吕肖锋,姚璐,朱旅云,等.米格列奈钙片治疗2型糖尿病的安全性及有效性的临床研究.临床药理学,2009,14(2)：175-179.
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[11]Ohnota H, Kitamura T, Kinukawa M, et al. A rapid-and short-acting hypoglycemic agent KAD-1229 improves post-prandial hyperglycemia and diabetic complications in streptozotocin-induced non-insulin-dependent diabetes mellitus rats. Jpn J Pharmacol, 1996,71(4):315-323.
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[1]Groop LC, Widen E, Ferrannini E. Insulin resistance and insulin deficiency in the pathogenesis of type 2 (non-insulin-dependent) diabetes mellitus:Errors of metabolism or of methods? Diabetologia.1993,36:1326-1331.
[2]Ward WK, Bolgiano DC, McKnight B, et al. Diminished β cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Chin Invest.1984,74(4): 1318-1328.
[3]DeFronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care.1992,15(3):318-368.
[4]Kelley D, Mokan M, Veneman T. Impaired postprandial glucose utilization in noninsulin-dependent diabetes mellitus. Metabolism.1994,43(12):1549-1557.
[5]Firth RG, Bell PM, Marsh HM, et al. Postprandial hyperglycemia in patients with noninsulin-dependent diabetes mellitus. Role of hepatic and extrahepatic tissues. J Chin Invest.1986,77(5):1525-1532.
[6]Asplund K, Wiholm BE, Lithner F. Glibenclamide-associated hypoglycaemia:A report on 57 cases. Diabetologia.1983,24(6):412-417.
[7]Ferner RE, Neil HA. Sulphonylureas and hypoglycaemia. Br Med J (Chin Res Ed).1988,296(6627):949-950.
[8]Barrett-Connor E, Ferrara A. Isolated postchallenge hyperglycemia and the risk of fatal cardiovascular disease in older women and men. The Rancho Bernardo Study. Diabetes Care.1998,21(8):1236-1239.
[9]Glucose tolerance and mortality:Comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE Study Group. European Diabetes Epidemiology Group. Diabetes Epidemiology:Collaborative analysis Of Diagnostic criteria in Europe. Lancet.1999,354(9176):617-621.
[10]Sunaga Y, Gonoi T, Shibasaki T D, et al. The effects of mitiglinide KAD-1229/, a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion:comparison with the sulfonylureas and nateglinide [J]. Eur J Pharm,2001,431(1):119-125.
[11]Ohnotal H, Kitamura T, Kinukawa M, et al. A Rapid-and Short-Acting Hypoglycemic Agent KAD-1229 Improves Post-Prandial Hyperglycemia and Diabetic Complication in Streptozotocin-Induced Non-Insulin-Dependent Diabetes Mellitus Rats. Jpn. J. Pharmacol.1996,71:315-323.
[12]Tahara A, Yokono AM, Shibasaki M. Effects of antidiabetic drugs in high-fat diet and streptozotocin-nicotinamide-induced type 2 diabetic mice.Eur J Pharmacol.2011, 655:108-116.
[13]Maruyama I, Tomiyama Y, u Maruyama K, et al. Effects of mitiglinide and sulfonylureas in isolated canine coronary arteries and perfused rat hearts. Eur J Pharmacol.2006,531:194-200.
[14]Ohnota H, Koizumi T, Tsutsumi N, et al. Novel rapid- and short-acting hypoglycemic agent, a calcium(2s)-2-benzyl-3-(cis-hexahydro-2-isoindolinylcarbonyl) propionate (KAD-1229) that acts on the sulfonylurea receptor:comparison of effects between KAD-1229 and gliclazide.J Pharmacol Exp Ther.1994,269(2):489-495.
[15]Lushan Y, Su Z. Determination of mitiglinide in rat plasma by high-performance liquid chromatography with UV detection. J Chromatogr B,2006,834(1-2):204-207.
[16]梁嘉碧,田媛,冯文周,等.米格列奈片人体药动学研究.中国药学杂志,2009,44(19)：1500-1503.
[17]刘婷立,冯婉玉,顾玲玲,等.HPLC-MS/MS法研究米格列奈钙片在健康人体内药代动力学.中国新药与临床杂志,2009,29(2)：225-228.
[18]汪志娟,李见春,董海军,等.米格列奈钙片单、多次给药人体药代动力学研究.安徽医药杂志,2009,13(9)：1028-1031.
[19]Yu L, Lu S, Lin Y, et al. Carboxyl-glucuronidation of mitiglinide by human UDP-glueuronosyltransferases[J]. Biochem Pharmacol,2007,73(11):1842-1851.
[20]牛晓方,郭瑞臣.新型Ⅱ型糖尿病治疗药-米格列奈.齐鲁药事,2007,26(11)：700-702.
[21]王广宇,朱旅云,马利成,等.米格列奈治疗2型糖尿病临床试验研究.临床内科杂志,2006,23(12)：812-814.
[22]吕肖锋,姚璐,朱旅云,等.米格列奈钙片治疗2型糖尿病的安全性及有效性的临床研究.临床药理学,2009,14(2)：175-179.
[23]Glucose tolerance and mortality:Comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE Study Group. European Diabetes Epidemiology Group. Diabetes Epidemiology:Collaborative analysis Of Diagnostic criteria in Europe. Lancet.1999,354(9176):617-621.
[24]Avignon A, Radauceanu A, Monnier L. Nonfasting plasma glucose is a better marker of diabetic control than fasting plasma glucose in type 2 diabetes. Diabetes Care.1997, 20(12):1822-1826.
[25]Zimmerman BR, Espenshade J, Fujimoto WY, et al. The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care.1996,19(Suppl 1):554--561.
[26]Tomoaki Y, Naoki K, Yoshi K, et al. Therapeutic efficacy of mitiglinide combined with once daily insulin glargine after switching from multiple daily insulin regimen of aspart insulin and glargine in patients with type 2 diabetes mellitus. Endocrine Journal, 2006,53(1):67-72.
[27]Abe M, Okada K, Maruyama T, et al. Efficacy and safety of mitiglinide in diabetic patients on maintenance hemodialysis. Endocrine Journal,2010,57(7):579-586.