格列齐特2种缓释片单次和多次给药 的药动学和生物利用度比较(英文)

目的:比较国产和进口格列齐特缓释片的人体药动学和相对生物利用度。方法:采用单次和多次给药的4周期双交叉设计,用液相色谱质谱联用法测定20名健康男性志愿者血浆中格列齐特的浓度。结果:单次口服国产和进口格列齐特缓释片后的药动学参数分别为:tmax为(7.2±s1.5)h和(6.9±1.4)h,cmax为(2.4±0.8)mg·L-1和(2.3±0.6)mg·L-1,t1/2为(13.4±1.2)h和(13.7±1.3)h,AUC0～60为(48±14)mg·h·L-1 和(48±14)mg·h·L-1,AUC0～∞为(51±15)mg·h·L-1和(50±14)mg·h·L-1,平均滞留时间(MRT)为(22.4±1.9)h和(22.78±1.9)h。多次(60mg,6d)口服国产和进口格列齐特缓释片后的稳态药动学参数分别为:tmax为(6.1±1.4)h和(6.5±1.4)h,cmax为(4.6±0.9)mg·L-1和(4.7±1.1) mg·L-1,cmin为(0.23±0.08)mg·L-1和(0.26±0.08)mg·L-1,稳态血药浓度均值(cav)为(1.6±0.3)mg·L-1和(1.6±0.3)mg·L-1,AUCss为(94±19)mg·h·L-1和(95±20)mg·h·L-1,波动度(DF)为(282±33)%和(283±43)%。单次和多次口服国产与进口格列齐特缓释片相对生物利用度分别为(102±9)%和(99±10)%。上述单次和多次给药的药动学参数经方差分析无显著差异(P>0.05)。结论:双单侧t检验表明2种制剂具有生物等效性。     

六味地黄丸对家兔体内格列齐特药动学的影响

目的研究六味地黄丸在家兔体内对格列齐特片代谢的影响。方法新西兰大白兔8只,每只予格列齐特80nag,po。经2周清洗期后,每只家兔予六味地黄丸每次8颗,po,tid,连续2周,第15天予相同剂量的格列齐特片。所有家兔均分别于给药前（0h）以及给予格列齐特片后不同时间点经耳缘静脉采血,HPLC法测定格列齐特的血浓度,DAS3．2．1计算药动学参数。结果格列齐特在家兔体内的药动学符合非房室模型。单用格列齐特家兔组,其tmax ρmax、AUC分别为（3．01±1．69）h、（51．91±8．38）mg·L^-1、（2551．08±15．58）mg·h·L^-1;联用六味地黄丸组,其tmax、ρmax、AUC分别为（1．04±1．06）h、（88．93±6．61）mg·L^-1、（1956．68±11．98）mg·h·L^-1。格列齐特在给予六味地黄丸前后的tmax、ρmax、AUC之间差异均有统计学意义（P〈0．05）。结论六味地黄丸对家兔体内格列齐特的药动学存在影响,可增加格列齐特的峰浓度,并且缩短其达峰时间。据此建议临床上两药合用时,应严密监测格列齐特浓度以及患者血糖值。     

格列齐特对氯沙坦钾血浆蛋白结合率的影响

目的 研究格列齐特对氯沙坦钾血浆蛋白结合率的影响。方法 采用平衡透析法并结合HPLC,测定未加和加入格列齐特后氯沙坦钾的人血浆蛋白结合率。结果 3种浓度下,未加格列齐特时氯沙坦钾的血浆蛋白结合率分别为97.4%,97.8%,98.2%,与格列齐特合用时,氯沙坦钾的血浆蛋白结合率依次为94.1%,94.8%,94.9%。结论 氯沙坦钾与格列齐特合用后,血浆蛋白结合率显著下降(P<0.01)。     

Optimal dosing of gliclazide—A model-based approach

Gliclazide was approved as a treatment for type 2 diabetes in an era before model-based drug development, and consequently, the recommended doses were not optimised with modern methods. To investigate various dosing regimens of gliclazide, we used publicly available data to characterise the dose-response relationship using pharmacometric models. A literature search identified 21 published gliclazide pharmacokinetic (PK) studies with full profiles. These were digitised, and a PK model was developed for immediate- (IR) and modified-release (MR) formulations. Data from a gliclazide dose-ranging study of postprandial glucose were used to characterise the concentration–response relationship using the integrated glucose–insulin model. Simulations from the full model showed that the maximum effect was 44% of the patients achieving HbA1c <7%, with 11% experiencing glucose <3 mmol/L and the most sensitive patients (i.e., 5% most extreme) experiencing 35 min of hypoglycaemia. Simulations revealed that the recommended IR dose (320 mg) was appropriate with no efficacy gain with increased dose. However, the recommended dose for the MR formulation may be increased to 270 mg, with more patients achieving HbA1c goals (i.e., HbA1c <7%) without a hypoglycaemic risk higher than the resulting risk from the recommended IR dose.     

化学原料药中19种金属杂质的检测研究

目的:以格列齐特为研究对象,建立化学原料药中19种金属杂质的测定方法。方法:采用电感耦合等离子体发射光谱法,供试品经微波消解前处理后测定。为克服各元素之间的光谱干扰,且保证检测灵敏度,将所有元素分为3个系统,确定合适的发射谱线和观测模式,同时对等离子参数进行优化。结果:在一定的浓度范围内,各元素谱线的发射强度均与浓度呈良好的线性关系,相关系数均大于0.999,加样回收率为76.6%～123.0%,检测限均满足测定的要求。结论:该方法专属性好,灵敏度高,准确快捷,可替代传统的重金属检查法,用于化学原料药中金属杂质的测定。     

羟丙基-β-环糊精对格列齐特增溶作用的研究

目的:研究羟丙基-β-环糊精(HP-β-CD)包合对难溶性药物格列齐特(GZ)溶解度和溶出度的增强作用。方法:分别采用研磨法、超声法和冷冻干燥法制备GZ的HP-β-CD包合物,测定其溶解度和溶出度,并与GZ原料药,GZ与HP-β-CD的物理混合物进行比较。用差热扫描量热法,红外光谱对包合物进行物相鉴别。结果:HP-β-CD与GZ形成包合物使其溶解度提高6.8倍。结论:HP-β-CD能大幅度地提高GZ的溶解度和溶出度。     

高效液相色谱法测定格列齐特缓释片的含量和有关物质

目的建立格列齐特缓释片的含量测定方法。方法采用HPLC法。结果线性范围为0．804-4．824μg（r=0．9996）,平均回收率为100．13％,RSD为1.33％（n=9）。结论本方法可用于格列齐特缓释片的含量测定。     

Effects of St John's wort and CYP2C9 genotype on the pharmacokinetics and pharmacodynamics of gliclazide

BACKGROUND AND PURPOSE: Patients commonly take complementary medicines in conjunction with conventional drugs without clear evidence of safety or the risk of herb-drug interactions. The aim of this study was to assess potential pharmacokinetic (PK) and pharmacodynamic (PD) interactions between St John's wort and gliclazide in healthy subjects with different cytochrome P450 2C9 (CYP2C9) genotypes. EXPERIMENTAL APPROACH: A crossover controlled study was conducted in 21 healthy subjects. Each received gliclazide (80 mg) either alone or during 15 days treatment with St John's wort. The area under the plasma concentration-time curve (AUC(0-infinity)), apparent clearance (CL/F) and elimination half-life (t 1/2) of gliclazide and incremental changes in glucose and insulin AUC(0-4) were compared. CYP2C9*2 and CYP2C9*3 alleles were identified using PCR followed by restriction enzyme digestion analysis. KEY RESULTS: St John's wort significantly altered gliclazide pharmacokinetics in all except for four healthy subjects. The mean ratio and 90% confidence interval (CI) of gliclazide AUC(0-infinity) and CL/F were 0.67 (0.55-0.81) and 1.50 (1.24-1.81), respectively, after St John's wort treatment. St John's wort decreased gliclazide t (1/2), with mean ratio and 90% CI of 0.85 (0.74-0.93). There were no significant changes in glucose or insulin AUC(0-4) after St John's wort treatment and no significant differences according to CYP2C9 genotype. CONCLUSIONS AND IMPLICATIONS: Treatment with St John's wort significantly increases the apparent clearance of gliclazide which is independent of CYP2C9 genotype. People with diabetes receiving this combination should be closely monitored to evaluate possible signs of reduced efficacy.     

Dynamics of Insulin Release and Microtubular-Microfilamentous System

Abstract. The effect of colchicine upon glucose-induced insulin release by the isolated perfused rat pancreas was examined in order to characterize the participation of the β-cell microtubular apparatus in the biphasic insulin secretory response to glucose. After a short pretreatment (25 min.) with a low colchicine concentration (2.10^-5M), both the early and late phases of glucose-induced insulin secretion were markedly enhanced. As either the concentration of colchicine or the length of the pretreatment period with this mitotic spindle-inhibitor were increased, the facilitating effect faded out and partial inhibition of insulin release was observed. However, colchicine, even at high concentration, markedly enhanced the residual early release of insulin evoked by glucose in the presence of diazoxide (0.05 mg/ml). These findings suggest that (i) a fraction of the early phase of insulin secretion completely escapes from the inhibitory effect of colchicine and may correspond, therefore, to a modality of hormonal release which does not involve the oriented intracellular translocation of secretory granules; and (ii) extensive disruption of the micro-tubular apparatus is associated with inhibition of insulin release, especially during the late phase of the secretory response to glucose.