阿魏酸长期给药后对大鼠灌服氯沙坦钾的药动学影响

目的 研究长期给药阿魏酸对大鼠体内氯沙坦及其代谢物E-3174的药动学影响。方法 12只健康♂ SD大鼠随机分成2组（每组6只）,试验组每天灌胃50 mg·kg^-1阿魏酸,连续诱导7 d;对照组灌胃等体积0.5%CMC-Na。第8天给药30 min后,给予氯沙坦钾（5 mg·kg^-1）。分别于给药前和给药后0.25,0.5,0.75,1,1.5,2,3,4,6,8,10,12,24 h大鼠尾静脉取血,血样处理后采用UPLC-MS/MS检测大鼠血浆中氯沙坦及E-3174的浓度。结果 虽然2组大鼠体内氯沙坦各项药动学参数对比均无统计学意义,但是试验组大鼠体内E-3174的AUC（0-t）、AUC（0-∞）和Cmax显著增高（P<0.05）;CL/F、Tmax显著降低（P<0.05）。结论 大鼠长期给药阿魏酸后虽然未能引起氯沙坦原形药物药动学的变化,但可使其活性代谢产物E-3174代谢减慢,浓度增高,药时曲线下面积增大。     

香叶木苷对格列苯脲在大鼠体内药动学的影响

目的 考察香叶木苷在大鼠体内对格列苯脲药动学的影响。方法 12只SD大鼠随机分为香叶木苷组和对照组，分别给予香叶木苷（325 mg·kg^-1，ig，qd）和同体积CMC-Na溶液7 d后，灌胃给予格列苯脲，于不同时间点采集血浆样品，测定血药浓度，DAS 2.0计算主要药动学参数，并进行统计学分析。结果 与对照组比，香叶木苷组C_max显著降低（P<0.05），t_max显著缩短（P<0.05），AUC_（0→t）和AUC_{（0→∞）}显著减少（P<0.05），CL显著增大（P<0.05），t_1/2差异不显著。结论 香叶木苷影响格列苯脲在大鼠体内的药动学过程，临床联合用药中应对格列苯脲的血药浓度进行监测，以避免潜在的药物相互作用风险。     

氯沙坦对2型糖尿病大鼠体内格列吡嗪药动学的影响

目的探讨氯沙坦对格列吡嗪在2型糖尿病大鼠体内药动学参数的影响。方法以高糖高脂饲料喂养、ip低剂量链脲佐菌素诱导2型糖尿病模型大鼠为研究对象,ig氯沙坦片5 mg/kg,给药1 h后ig格列吡嗪5 mg/kg,于给药后1、2、3、4、5、6、8、10、12h采集血浆样品,采用HPLC法测定血浆中的格列吡嗪质量浓度,绘制其血浆平均药物浓度–时间曲线;计算格列吡嗪在大鼠体内的主要药动学参数。结果与健康大鼠比较,格列吡嗪在2型糖尿病大鼠体内消除半衰期明显延长(P0.05)。在2型糖尿病大鼠中,与单用格列吡嗪比较,格列吡嗪的达峰浓度(Cmax)、时量曲线下面积(AUC)明显增加(P0.05),达峰时间(tmax)明显减小(P0.05)。结论在糖尿病病理状态下,格列吡嗪的药动学发生了一定的改变。联合用药时,氯沙坦可明显提高格列吡嗪的血药浓度和生物利用度。     

格列本脲检测方法的研究进展

目的 总结和探讨格列本脲分析方法的研究发展方向。方法 通过查阅相关文献和归纳总结,对检测格列本脲的多种分析方法进行阐述,比较不同方法的优缺点,并介绍格列本脲降解产物的分析现状。结果 目前格列本脲检测技术有了很大提高,测定方法更加丰富。结论 高灵敏度、高选择性、联用技术是格列本脲分析方法的发展方向。关键词:格列本脲;检测方法;研究进展     

UPLC-Q-TOF-MS快速检测降糖类中成药中非法添加的盐酸苯乙双胍、格列本脲和盐酸吡格列酮

目的 建立UPLC Q-TOF MS快速检测降糖类中成药中非法添加的盐酸苯乙双胍、格列本脲、盐酸吡格列酮。方法 采用Aglient ZORBAX SB C₁₈色谱柱(2.1 mm×100 mm,1.8 μm),甲醇-10 mmol·L^-1醋酸铵溶液(含0.1%甲酸)为流动相,梯度洗脱;离子源为ESI,正离子检测方式;利用保留时间、DAD紫外光谱图、一级质谱和二级质谱碎片信息四方面信息并结合数据库,对10种降糖类化学成分进行质谱定性,同时对5批降糖类中成药中非法添加的盐酸苯乙双胍、格列本脲、盐酸吡格列酮进行定性、定量测定,并对这3种化学物质的裂解规律进行初步解析。结果 5批胶囊中均检测出盐酸苯乙双胍、格列本脲、盐酸吡格列酮3种成分。结论 本方法专属性强、灵敏度高、操作简便,可用作降糖类中成药中非法添加盐酸苯乙双胍、格列本脲、盐酸吡格列酮的检测。     

C57BL/6J糖尿病小鼠模型的优化研究

目的 优化链脲佐菌素（streptozotocin,STZ）诱导的C57BL/6J糖尿病小鼠模型。方法 采用单用不同剂量STZ（180 mg·kg^-1单次给药和275 mg·kg^-1均分5次,每次55 mg·kg^-1,连续5 d）或4周高脂饮食联合不同剂量STZ（50 mg·kg^-1单次给药;100 mg·kg^-1单次给药;150 mg·kg^-1单次给药;200 mg·kg^-1均分2次给药,间隔72 h）,建立糖尿病小鼠模型,检测各组小鼠空腹血糖、体质量、日饮水量及日进食量,比较各组造模成功率及稳定性。结果 STZ 180 mg·kg^-1单次给药、高脂饮食4周+STZ 150 mg·kg^-1单次给药、高脂饮食4周+STZ 200 mg·kg^-1均分2次给药得到的糖尿病小鼠模型,其高血糖的持续时间较长且稳定。结论 STZ 180 mg·kg^-1单次给药是较为理想的1型糖尿病模型;4周高脂饮食联合STZ 150 mg·kg^-1单次给药或200 mg·kg^-1均分2次给药均是较为理想的2型糖尿病模型。     

瑞舒伐他汀对格列喹酮在2型糖尿病大鼠体内药动学参数的影响

目的 探究瑞舒伐他汀对格列喹酮在2型糖尿病大鼠体内药动学参数的影响。方法 采用高糖高脂饲料喂养与ip低剂量链脲佐菌素（40 mg/kg）相结合的方法制备SD大鼠2型糖尿病模型。2型糖尿病大鼠先ig瑞舒伐他汀（10 mg/kg）,0.5 h后再ig格列喹酮（15 mg/kg）,于给药后0.5、1.5、2、2.5、4、6、8 h颈动脉取血。采用高效液相色谱法测定大鼠血浆中格列喹酮的浓度,绘制血药浓度–时间曲线,计算药动学参数。结果 在2型糖尿病大鼠中,与格列喹酮单用相比,与瑞舒伐他汀联用之后,格列喹酮的t_1/2明显延长（P＜0.01）,血浆清除率（CL）明显降低（P＜0.01）,达峰浓度（C_max）、药–时曲线下面积（AUC）明显增加（P＜0.01）。结论 瑞舒伐他汀和格列喹酮联用后,可明显改变格列喹酮在2型糖尿病大鼠体内的药动学参数,提高其血药浓度。因此,当两药联用时,应特别注意潜在的药物相互作用和格列喹酮的使用剂量。     

近红外光谱技术测定非法添加的格列本脲

摘 要 目的:建立非法添加格列本脲产品的近红外检测方法。方法: 以格列本脲对照品近红外光谱图为参照光谱,选择特征谱段,根据已知样本的近红外光谱与参照光谱的相关系数、格列本脲的有效剂量,确定阈值,建立检测模型。结果:通过验证,检测模型准确率较高。结论:通过近红外特征谱段相关系数法建立的检测模型,可用于非法添加格列本脲产品的快速检测。     

两种格列吡嗪胶囊的人体生物等效性研究

目的建立测定人血浆中格列吡嗪浓度的高效液相色谱法，并对供试制剂格列吡嗪胶囊与参比制剂格列吡嗪胶囊的生物等效性进行评价。方法血样处理采用固相萃取方法，萃取小柱用甲醇活化后加入血浆1.0 mL，过柱后用含20%甲醇的水溶液1.0 mL洗涤，弃去洗涤液，再用1.0 mL甲醇洗脱收集，收集液于60 ℃水浴挥干，最后用100 μL甲醇溶解，取20 μL进样。色谱条件：色谱柱为ODS C18柱(5 μm，4.6 mm×150 mm );流动相为纯化水(用冰醋酸调pH值为3.65)-乙腈(51∶49);流速为1.0 mL·min-1;紫外检测波长为275 nm。人体药动学试验采用双周期交叉设计方案，将18名志愿受试者随机平均分成两组，分别口服格列吡嗪供试胶囊和参比胶囊10 mg。结果格列吡嗪的线性范围为20～960 ng· mL^-1，r＝0.999 9，最低检测限为20 ng· mL^-1，方法回收率为98.2%～105.7%，日内、日间RSD均＜10%，供试制剂与参比制剂格列吡嗪胶囊的主要药动学参数差异无显著性。结论该方法灵敏度高，特异性强，重现性好。供试与参比制剂格列吡嗪胶囊具有生物等效性。     

HPLC-MS测定人血浆中格列本脲的浓度及不同剂量格列本脲的药物动力学

目的建立血浆中灵敏的格列本脲HPLC-MS测定法,研究不同剂量格列本脲片在正常人体的药物动力学。方法以格列美脲为内标,血浆样品经乙醚萃取后,经MACHEREY-NAGEL C18柱分离,采用质谱检测器检测,18名健康受试者采用随机交叉,单剂量口服格列本脲片2.5 mg或10 mg后测定其血药浓度,研究不同剂量格列本脲的药物动力学。结果格列本脲与内标分离度好,内源性杂质不干扰测定。在0.51-852μg·L^-1格列本脲浓度与峰面积比的线性关系良好,最小可定量浓度为0.51μg·L^-1,回收率为100.68%-108.7%,日内RSD为2.1%-3.4%;日间RSD为1.9%-4.9%。单次服用格列本脲片2.5 mg或10 mg后AUC0→48分别为（533.5±247.0）h·μg·L^-1和（1 982.9±893.1）h·μg·L^-1,Cmax分别为（94.1±19.1）μg·L^-1和（349.6±82.9）μg·L^-1,tmax分别为（1.90±0.40）h和（1.9±0.4）h,t1/2为（10.2±4.4）h和（9.4±1.8）h。结论HPLC-MS方法简单,准确度高,灵敏度好,可用于小剂量格列本脲在人体内药物动力学研究。单次给予格列本脲2.5 mg·次^-1或10 mg·次^-1,其人体内的药物动力学规律无明显改变。     

齐墩果酸对氟伐他汀在大鼠体内药动学的影响

目的 探讨齐墩果酸对氟伐他汀在大鼠体内的药代动力学影响。方法 将16只健康大鼠随机分为单药组(5.0mg?kg-1 氟伐他汀)和联合用药组(5.0mg?kg-1氟伐他汀 60mg?kg-1 齐墩果酸),单药组和联合用药组分别灌胃空白溶剂和齐墩果酸5天,每天一次。第6天两组均给予氟伐他汀灌胃,给药后不同时间点采血,LC-MS法测定大鼠体内血药浓度,比较两组间主要的药代动力学参数。结果 与单药组比较,联合用药组氟伐他汀主要药代动力学参数Cmax、AUC0-t参数值显著上升,组间比较差异具有统计学意义(P＜0.05)。结论 联合应用齐墩果酸可能影响大鼠体内氟伐他汀的药代动力学特性。     

疾病以及配伍对人参皂苷在大鼠体内的药动学影响

目的 建立SD大鼠血浆中人参皂苷Rb1、Rb2和Rg1的HPLC分析方法,对比分析配伍白术挥发油前后,人参皂苷在慢性萎缩性胃炎模型大鼠体内药动学特征。方法 SD大鼠分为4组,其中单用正常组和单用模型组均给药人参总皂苷292 mg·kg^-1,配伍正常组和配伍模型组均给药人参总皂苷292 mg·kg^-1和白术挥发油0.1 mL·kg^-1。于给药前和给药后不同时间点进行眼眶取血,采用HPLC测定各成分的血药浓度,并采用Winnolin 6.3软件计算其药动学参数。结果 与单用正常大鼠比较,单用模型组大鼠体内人参皂苷Rb1的C_max和AUC值降低,T_max、T_1/2以及MRT增加,人参皂苷Rb2和Rg1则呈现出AUC增加的变化;而配伍正常组大鼠体内人参皂苷Rb1、Rb2和Rg1的C_max和AUC值均增加,T_max、T_1/2以及MRT值均缩短。与单用模型组大鼠比较,配伍模型组大鼠体内人参皂苷Rb1和Rg1的C_max和AUC值均增加,T_max、T_1/2以及MRT值均降低。结论 在相同给药剂量下,疾病状态机体对人参皂苷的吸收和代谢呈现缓慢趋势,而配伍后能促进皂苷成分在体内的吸收,同时加快代谢消除,为人参的临床用药提供参考依据。     

LC-MS/MS测定大鼠血浆中K15的浓度及其在药动学研究中的应用

目的 建立SD大鼠血浆中（3AS,4S,6AR）-四氢-4-甲氧基-呋喃并[3,4-B]呋喃-2（3H）-酮（K15）的LC-MS/MS测定方法,并进行K15的药动学研究。方法 分别灌胃及静脉注射给予大鼠不同剂量K15后,从眼眶静脉丛取血,并采用LC-MS/MS测定大鼠血浆中K15的浓度变化。利用DAS药动学软件拟合主要药动学参数AUC、C_max、T_max、T_1/2等。结果 大鼠血浆中的内源性杂质不干扰K15的测定,日内精密度4.53%~6.60%,日间精密度5.19%~8.14%,准确度为96.10%~102.49%。K15的线性范围为25~1 000 ng·mL^-1,r=0.998 5。K15的定量下限为25 ng·mL^-1（RSD=12.7%,n=6）。150,450和1 000 mg·kg^-1灌胃给药的生物利用度分别为79.5%,44.4%和57.0%。结论 该方法适用于K15在大鼠中的药动学研究。K15在大鼠中的药动学为非线性动力学,灌胃给予大鼠后在其体内具有一定的系统暴露量,但没有随给药剂量呈线性增加。在给药剂量为100和450 mg·kg^-1时,其在体内的C_max没有显著性增高,但是在1 000 mg·kg^-1时,C_max显著增加。随着给药剂量的增加,K15在大鼠体内的T_1/2显著增加,提示K15在大鼠体内的暴露时间随剂量的增加显著延长。     

Fluconazole but not itraconazole decreases the metabolism of losartan to E-3174

Objective: Losartan is metabolised to its active metabolite E-3174 by CYP2C9 and CYP3A4 in vitro. Itraconazole is an inhibitor of CYP3A4, whereas fluconazole affects CYP2C9 more than CYP3A4. We wanted to study the possible interaction of these antimycotics with losartan in healthy volunteers. Methods: A randomised, double-blind, three-phase crossover study design was used. Eleven healthy volunteers ingested orally, once a day for 4 days, either itraconazole 200 mg, fluconazole (400 mg on day 1 and 200 mg on days 2–4) or placebo (control). On day 4, a single 50-mg oral dose of losartan was ingested. Plasma concentrations of losartan, E-3174, itraconazole, hydroxy-itraconazole and fluconazole were determined over 24 h. The blood pressure and heart rate were also recorded over 24 h. Results: The mean peak plasma concentration (C_max) and area under the curve [AUC(0∞)] of E-3174 were significantly decreased by fluconazole to 30% and to 47% of their control values, respectively, and the t_1/2 was increased to 167%. Fluconazole caused only a nonsignificant increase (23–41%) in the AUC and t_1/2 of the unchanged losartan. Itraconazole had no significant effect on the pharmacokinetic variables of losartan or E-3174. The ratio AUC(0∞)_E-3174/AUC(0∞)_losartan was 60% smaller during the fluconazole than during the placebo and itraconazole phases. No clinically significant changes in the effects of losartan on blood pressure and heart rate were observed between fluconazole, itraconazole and placebo phases. Conclusion: Fluconazole but not itraconazole interacts with losartan by inhibiting its metabolism to the active metabolite E-3174. This implicates that, in man, CYP2C9 is a major enzyme for the formation of E-3174 from losartan. The clinical significance of the fluconazole–losartan interaction is unclear, but the possibility of a decreased therapeutic effect of losartan should be kept in mind. Received: 4 June 1997 / Accepted in revised form: 10 September 1997     

大鼠重复ig给予N-［（3-烯丙基-2-羟基）苯亚甲基-2-（4-苄基-高哌嗪-1-基）乙酰肼富马酸盐的药动学研究

目的 采用高效液相色谱-串联质谱法（HPLC-MS/MS）测定SD大鼠血浆中N-［（3-烯丙基-2-羟基）苯亚甲基］-2-（4-苄基-高哌嗪-1-基）乙酰肼富马酸盐（SM-1）,并计算大鼠重复ig给药的药动学参数,评价SM-1的药动学特征。方法 将60只健康SPF级SD大鼠随机分为阴性对照组、溶媒对照组和SM-1低、中、高剂量组,每组16只动物（阴性对照组和溶媒对照组为6只动物）,雌雄各半。每天ig给药1次,各组分别给予水、溶媒或SM-1 50、100、200 mg·kg^-1,给药体积10 mL·kg^-1,连续给药4周,于首次给药和末次给药阶段进行药动学采血测定。采用经验证的HPLC-MS/MS法测定SD大鼠血浆中SM-1浓度。使用Phoenix WinNonlin 7.0软件进行血药浓度-时间数据分析与药动学参数计算。结果 SD大鼠ig给予SM-1后,在50～200 mg·kg^-1剂量,SD大鼠体内的平均峰浓度（C_max）及药时曲线下面积（AUC_0～t）随剂量的增加而增加,各剂量组动物平均C_max及AUC_0～t比值与剂量比相近。连续给药后,低、中、高剂量组均未出现明显的蓄积。雌性大鼠SM-1的暴露高于雄性大鼠。结论 连续给药28 d后,SM-1在大鼠体内未出现明显的蓄积,雌性大鼠SM-1的暴露高于雄性大鼠。     

Lack of polymorphism of the conversion of losartan to its active metabolite E-3174 in extensive and poor metabolizers of debrisoquine (cytochrome P450 2D6) and mephenytoin (cytochrome P450 2C19)

Objective: Losartan was given to subjects with known phenotypes of the polymorphic enzymes CYP2D6 and CYP2C19 to study any possible influence on the metabolism of the drug. Methods: Plasma concentrations of losartan and E-3174 were studied after oral intake of 50 mg losartan in 24 healthy, male, Swedish Caucasian subjects who were extensive or poor metabolizers (EM/PM) of debrisoquine [cytochrome P450 2D6 (CYP2D6)] or mephenytoin [cytochrome P450 2C19 (CYP2C19)]. Results: The areas under the curve (AUC_∞) of losartan and E-3174 did not differ between poor and extensive metabolizers of debrisoquine or mephenytoin, respectively. Conclusion: About 14% of the antihypertensive drug losartan is metabolized to the active carboxylic acid metabolite E-3174, which contributes to the effect of losartan. The present study suggests that CYP2D6 and CYP2C19 are not involved to any major extent in the in vivo conversion of losartan to E-3174. Received: 21 April 1998 / Accepted in revised form: 16 December 1998     

Effects of Ginkgo leaf tablets on the pharmacokinetics of losartan and its metabolite EXP3174 in rats and its mechanism

Context: Ginkgo leaf tablets (GLTs) and losartan are often simultaneously used for the treatment of hypertension in Chinese clinics. However, the herb–drug interaction between GLT and losartan is still unknown.

Objective: This study investigates the effects of GLT on the pharmacokinetics of losartan and its metabolite EXP3174 in rats and its potential mechanism.

Materials and methods: The pharmacokinetic profiles of losartan and EXP3174 of orally administered losartan (10?mg/kg) with or without GLT pretreatment (80?mg/kg/day for 10?days) in Sprague–Dawley rats were determined. In vitro, the effects of GLT on the metabolic stability of losartan were investigated with rat liver microsomes.

Results: The C_max (1.22?±?0.25 vs 1.85?±?0.37?μg/mL) and the AUC_(0–t) (6.99?±?1.05 vs 11.94?±?1.79?mg·h/L) of losartan increased significantly (p?C_max (1.05?±?0.19 vs 0.72?±?0.12?μg/mL) of EXP3174 decreased significantly (p?t_1/2 of losartan was prolonged significantly from 3.94?±?0.62 to 4.75?±?0.52?h (p?Discussion and conclusions: The results indicate that GLT might increase the plasma concentration of losartan and decrease the concentration of EXP3174 through inhibiting the metabolism of losartan.     

Effects of berberine on the pharmacokinetics of losartan and its metabolite EXP3174 in rats and its mechanism

Context: Losartan and berberine (BBR) are often simultaneously used for the treatment of senile diabetic nephropathy in clinics. However, the potential herb–drug interaction between losartan and BBR is unknown.

Objective: This study investigates the influence of BBR on the pharmacokinetics of losartan and EXP3174, and investigates the effects of BBR on the metabolic stability of losartan.

Materials and methods: The pharmacokinetic profiles losartan and EXP3174 of orally administered losartan (10?mg/kg) with and without pretreatment with BBR (20?mg/kg) within 24?h were determined in Sprague-Dawley rats. The inhibitory effects of BBR on the metabolic stability of losartan were investigated using rat liver microsomes.

Results: The C_max (1.26?±?0.37 versus 1.96?±?0.45?mg/L) and the AUC_(0–t) (8.25?±?0.89 versus 12.70?±?1.42?mg h/L) of losartan were significantly (p?<?0.05) increased by BBR compared to the control, while the C_max (0.97?±?0.15 versus 0.77?±?0.06?mg/L) of EXP3174 was significantly decreased compared to the control (p?<?0.05). The T_max of losartan was prolonged from 0.41?±?0.12 to 0.52?±?0.18?h, but the difference was not significant. However, the T_max of EXP3174 was decreased significantly (p?<?0.05) from 8.14?±?0.36 to 3.33?±?0.28?h. The metabolic stability of losartan was increased from 37.4 to 59.6?min.

Discussion and conclusion: We infer that BBR might increase the plasma concentration of losartan and decrease the concentration of EXP3174 through inhibiting the activity of CYP3A4 or CYP2C9.     

葛兰心宁软胶囊联合双嘧达莫治疗冠心病心绞痛的临床研究

目的探讨葛兰心宁软胶囊联合双嘧达莫片治疗冠心病心绞痛的临床疗效。方法选择2019年6月—2021年6月在南阳南石医院治疗的84例冠心病心绞痛患者,根据用药的差别分成对照组(42例)和治疗组(42例)。对照组口服双嘧达莫片,50 mg/次,3次/d;治疗组在对照组基础上口服葛兰心宁软胶囊,1.16 g/次,2次/d。两组均经4周治疗。观察两组患者临床疗效,比较治疗前后两组患者心绞痛发作次数和持续时间,GQOLI-74、SF-36、SAQ和临床症状积分,及血清C反应蛋白(CRP)、可溶性CD40配体(sCD40L)、白细胞介素-18(IL-18)、髓过氧化酶(MPO)、人可溶性细胞黏附分子(sICAM-1)和妊娠相关血浆蛋白-A(PAPP-A)水平。结果经治疗,对照组总有效率为80.95%,显著低于治疗组的97.62%(P<0.05)。经治疗,两组心绞痛发作次数、持续时间均显著减少(P<0.05),但以治疗组减少最明显(P<0.05)。经治疗,两组GQOLI-74、SF-36和SAQ积分明显升高,临床症状积分明显降低(P<0.05),但治疗组积分明显好于对照组(P&...