Pharmacokinetic and pharmacodynamic characterization of gliclazide in healthy volunteers

Pharmacokinetic and pharmacodynamic properties of gliclazide were studied after an oral administration of gliclazide tablets in healthy volunteers. After an overnight fasting, gliclazide tablet was orally administered to 11 volunteers. Additional 10 volunteers were used as a control group (i.e., no gliclazide administration). Blood samples were collected, and the concentration determined for gliclazide and glucose up to 24 after the administration. Standard pharmacokinetic analysis was carried out for gliclazide. Pharmacodynamic activity of the drug was expressed by increase of glucose concentration (deltaPG), by area under the increase of glucose concentration-time curve (AUC(deltaPG)) or by the difference in increase of glucose concentration (D(deltaPG)) at each time between groups with and without gliclazide administration. Pharmacokinetic analysis revealed that Cmax, Tmax, CL/F (apparent clearance), V/F (apparent volume of distribution) and half-life of gliclazide were 4.69+/-1.38 mg/L, 3.45+/-1.11 h, 1.26+/-0.35 L/h, 17.78+/-5.27 L, and 9.99+/-2.15 h, respectively. When compared with the no drug administration group, gliclazide decreased significantly the AUC(deltaPG) s at 1, 1.5, 2, 2.5, 3 and 4 h (p<0.05). The deltaPGs were positively correlated with AUC(gliclazide) at 1 and 1.5 h (p<0.05), and the correlation coefficient was maximum at 1 h (r = 0.642) and gradually decreased at 4 h after the administration. The AUC(deltaPG)s were positively correlated with AUC(gliclazide) at 1, 2, 3 and 4 h (p<0.05), and the maximum correlation coefficient was obtained at 2 h (r=0.642) after the administration. The D(deltaPG) reached the maximum at 1 h, remained constant from 1 h to 3 h, and decreased afterwards. Therefore, these observations indicated that maximum hypoglycemic effect of gliclazide was reached at approximately at 1.5 h after the administration and the effect decreased, probably because of the homeostasis mechanism, in health volunteers.     

Effect of insulin and gliclazide on glucose utilization by a perfused intestine-pancreas preparation isolated from diabetic and non-diabetic rats

The effect of insulin (40 U/ml) and gliclazide (200 g/ml) on intestinal glucose metabolism was investigated by using an in vitro perfuse intestine-pancreas preparation isolated from normal or streptozotocin-diabetic rats. Glucose, lactate and alanine were measured enzymatically in the portal effluent. The glucose retained by the perfused preparation was reduced (P<0.05) in diabetic versus control rats. The portal lactate levels were not modified, but alanine portal levels were increased (P<0.05) in diabetic versus control rats. In the diabetic rats, the level of glucose retained by the preparations was increased (P<0.05) by the presence of insulin, and insulin plus gliclazide in the perfusate. In the presence of insulin and/or gliclazide, the portal lactate levels were not modified, but the alanine levels were reduced (P<0.05) to normal values. In preparations from non-diabetic rats, the level of glucose retained was increased (P<0.05) by gliclazide and insulin plus gliclazide, without modification of the portal lactate and alanine levels. In conclusion, the results show that both insulin and gliclazide increased glucose utilization by perfused intestine-pancreas preparations isolated from diabetic rats. The effect was enhanced when both substances were present simultaneously in the perfusion medium.Presented in part at the 26th annual meeting of the European Association for the Study of Diabetes, Copenhagen, 10–13 September 1990, and at the 4th meeting of the Mediterranean Group for the Study of Diabetes, Madrid, 4–7 March 1993     

不同厂家格列齐特片溶出度考察

目的 :比较6厂家格列齐特片的溶出度 ,为临床选用提供参考。方法 :采用分光光度法分别测定A、B、C、D、E、F厂格列齐特片的累积溶出度 ,绘制其溶出曲线 ,计算参数T50、Td、m的值 ,并对T50、Td 值进行两两比较。结果 :E厂格列齐特片的T50、Td 值与其它5厂有显著性差异 (P<0 01) ,其余5厂格列齐特片的T50、Td 值间无显著性差异 (P>0 05)。其中 ,E厂格列齐特片在180min时的累积溶出率<75 %,不符合《中国药典》规定 ,其它5厂格列齐特片的溶出度均符合规定。结论 :建议有关厂家对影响制剂溶出度的辅料及生产工艺进行改进 ,以提高产品质量。     

Effects of combination of insulin and acarbose compared with insulin and gliclazide in type 2 diabetic patients

In this prospective study we aimed to compare insulin plus acarbose with insulin plus gliclazide with respect to their effect on insulin requirement, lipid profiles and body mass index (BMI) while achieving good glycemic control. Forty patients with type 2 diabetes mellitus who were on conventional insulin therapy (subcutaneous insulin therapy consisting of regular and NPH insulin, two times a day) were included in the study. They were randomized to double blind treatment with insulin in combination with gliclazide or acarbose for 6 months. For both groups, acceptable glycemic control was achieved at the end of study period. The mean HbA_1c levels decreased from 8.32±0.26 to 7.13±0.18% in acarbose group and 8.6±0.15 to 7.48±0.21% in the gliclazide group. The difference between groups was not significant (P 0.29). In the acarbose group, total cholesterol and LDL concentration decreased significantly while other parameters did not change. In the gliclazide group, HDL levels decreased significantly from 46.6±2.48 mg/dl to 41.3±2.09 mg/dl (P 0.001) BMI increased significantly from 27.60±1.21 kg/m² to 28.69±1.26 kg/m². (P 0.003) Total daily insulin dose was not changed in the acarbose group significantly, but increased from 42.6±2.73 to 49.27±3.58 U/day, which was significant in gliclazide group of (P 0.016). In the acarbose group, there were no significant differences between responders and nonresponders with respect to fasting and stimulated C-peptide, HbA_1c levels and baseline BMI values. But in the gliclazide group, baseline BMI values were significantly higher in the nonresponding group compared to responders (P 0.02). In conclusion, combination of insulin with acarbose can be a good alternative for type 2 diabetic patients on insulin therapy; seems more beneficial than combination with gliclazide; may have advantage of achieving good glycemic control without increasing insulin dose and BMI; also may have the advantage of providing a decrease in LDL level, which are all important to prevent atherosclerosis. Received: 29 January 1999 / Accepted in revised form: 19 May 1999     

Development and validation of a new analytical HPLC method for simultaneous determination of the antidiabetic drugs,metformin and gliclazide

An efficient and simple HPLC method has been developed and validated for the simultaneous determination of gliclazide and metformin hydrochloride in bulk and was applied on marketed metformin and gliclazide products. The mobile phase used for the chromatographic runs consisted of 20 mM ammonium formate buffer (pH 3.5) and acetonitrile (45:55, v/v) The separation was achieved on an Alltima CN (250 mm × 4.6 mm x5μ) column using isocratic mode. Drug peaks were well separated and were detected by a UV detector at 227 nm. The method was linear at the concentration range 1.25–150 μg/ml for gliclazide and 2.5–150 μg/ml for metformin respectively. The method has been validated according to ICH guidelines with respect to system suitability, specificity, precision, accuracy and robustness. Metformin limit of detection (LOD) and limit of quantification (LOQ) were 0.8 μg/ml and 2.45 μg/ml respectively while LOD and LOQ for gliclazide were 0.97 μg/ml and 2.95 μg/ml respectively.     

RP-HPLC测定格列齐特缓释片的血药浓度

目的：采用反相高效液相色谱法（RP—HPLC）测定格列齐特缓释片的血药浓度。方法：以ODS C18为固定相,甲醇-0．01M NaH2PO4缓冲液（1．0ml／L磷酸）（60：40）为流动相,紫外检测波长为229nm。结果：在0．0625—8．0000μg／ml浓度范围线性良好,最低检测浓度为0．0625μg／ml。其相对回收率（n=5）大于91．3％,日内差（n=5）及日间差（n=5）RSD分别小于6．9％和6．5％。生物样品稳定性试验变异系数在15％以下。结论：RP—HPLC法简便、快速、灵敏度高,可用于格列齐特缓释片的人体药代动力学研究和生物利用度测定,为临床用药提供依据。     

格列齐特缓释片治疗2型糖尿病的疗效观察

目的：探讨格列齐特缓释片治疗2型糖尿病患者后血糖、糖化血红蛋白及C肽（C-P）等指标的变化。方法：2005年2月-2006年12月在我院门诊及住院的2型糖尿病患者78例,随机分为两组,格列齐特缓释片治疗组48例和格列苯脲治疗组30例进行疗效观察。结果：经12周的治疗,格列齐特组与格列苯脲组两组之间的FBG、2hBG、HbA1c、FC-P、2hC-P没有显著差异（P〉0.05）,但低血糖发生率格列齐特组为4.17%,格列苯脲组为40.00%（P〈0.01）。结论：格列齐特缓释片与格列苯脲的降糖效果相似,但安全性更好。     

Effect of gliclazide immobilization into layered double hydroxide on drug release

This paper deals with a new hydrotalcite-like compound used as a matrix to improve dissolution rate of the poorly water-soluble drug gliclazide and to administer at the same time micro- and oligo-elements useful to improve insulin performance. Gliclazide is a second-generation sulfonylurea compound used in the treatment of type II diabetes mellitus. As a consequence of the poor water solubility, its absorption is limited. Thus, a new hydrotalcite-like compound containing Zinc and Chromium, micronutrients directly involved in the physiology of insulin and in the carbohydrate, lipid and protein metabolism, was synthesized. The gliclazide-hydrotalcite-like clay nanohybrid was prepared via ion-exchange in its nitrate form and was characterized by inductively coupled plasma-optical emission spectrometry and thermogravimetric analysis. The drug loading resulted in 42.9% (w/w). As a consequence of the intercalation, the interlayer distance of the host increased from 0.89 nm (interlayer distance of nitrate form) to 1.5 nm. The intercalation product was submitted to solubility measurements and in vitro dissolution test. A remarkable improvement of the apparent solubility and dissolution rate in comparison to the crystalline drug was observed in acid fluids (pH 1.2 and 3). The presence of chromium and zinc cations was also found in the medium. These results showed that the hybrid nanostructure could represent a promising system to improve drug dissolution rate and to release cations involved in the performance of insulin.     

格列齐特固体共熔体的热分析研究

目的通过热分析技术证实共熔体的形成。方法按照差示扫描量热分析(DSC)和热重分析(TG)方法分别测定乳糖、格列齐特以及乳糖和格列齐特不同比例混合样。结果DSC曲线和TG曲线证明乳糖和格列齐特一定比例下形成共熔体。结论乳糖和格列齐特一定比例下经高速研磨混合的样品形成了共熔体;采用该工艺技术可显著提高难溶性药物主药格列齐特的溶出速率。     

格列齐特片(Ⅱ)鉴别与含量测定方法改进

目的:改进格列齐特片(Ⅱ)现有质量标准中鉴别与含量测定的方法。方法:采用紫外-可见分光光度法代替电位滴定法,溶剂为乙醇,检测波长为228nm,对格列齐特片(Ⅱ)进行鉴别和含量测定。结果:鉴别时无需前处理;改进后方法格列齐特检测浓度的线性范围为4.38～26.28μg·mL-1(r=0.9987);平均回收率为100.06%,精密度为0.17%。结论:与原有方法比较,本方法操作更简便安全,且结果准确,可用于该制剂的鉴别和质量控制。