注射用丹参总酚酸(冻干)对人CYP450酶和P-糖蛋白体外抑制作用及对大鼠CYP1A2和CYP3A体内诱导作用(英文)

目的探讨注射用丹参总酚酸(冻干)(SLI)对人CYP450酶和P-糖蛋白体外抑制作用以及对大鼠CYP1A2和CYP3A体内诱导作用。方法①应用P450-GloTMCYP450检测试剂盒,通过化学发光法测定SLI和经典抑制剂对细胞色素P4501A2(CYP1A2),CYP2D6,CYP3A4,CYP2C19和CYP2C9的IC50值,通过比较SLI和经典抑制剂对相应细胞色素P450亚型的IC50值来判断SLI对人CYP450酶的体外抑制作用。②Wistar大鼠分别iv给予SLI 3,10和30 mg·kg-1和诱导剂苯巴比妥钠20 mg·kg-1,采用探针底物法,通过比较代谢产物的生成速率来评价SLI对大鼠CYP1A2和CYP3A的诱导作用。③应用ATP酶检测试剂盒,通过化学发光法测定ATP酶活性来评价SLI是否为P-gp的底物或抑制剂。结果①CYP1A2,CYP2C9,CYP2C19,CYP2D6和CYP3A4抑制剂的IC50与SLI对其的IC50进行比较(CYP1A2:0.12μmol·L-1vs 840μmol·L-1;CYP2C9:3.362μmol·L-1vs 704μmol·L-1;CYP2C19:3.236μmol·L-1vs 306μmol·L-1;CYP2D6:0.117μmol·L-1vs 2660μmol·L-1;CYP3A4:0.078μmol·L-1vs 1780μmol·L-1)。②与空白对照组(86.4±6.3)nmol·g-1.min-1相比,SLI 3,10和30 mg·kg-1组CYP1A2活性分别为83.4±6.6,82.5±4.0和(83.4±6.6)nmol·g-1.min-1。与空白对照组(16.1±0.9)nmol·g-1.min-1比较,SLI 3,10和30 mg·kg-1组CYP3A活性分别为15.7±0.6,15.9±0.7和(15.9±1.0)nmol·g-1.min-1,无显著性差异。③以临床血药浓度为依据设计的一系列浓度的SLI 0.0002,0.0006,0.002,0.006,0.017,0.052,0.156和0.468 g.L-1的ATP酶活性分别与空白对照组进行比较(5.8,5.3,5.8,5.5,5.8,5.2,,5.8,5.3,vs 5.75μmol·g-1.min-1),无显著性差异。结论SLI临床给药剂量既不能体外抑制人CYP1A2,CYP2D6,CYP3A4,CYP2C19和CYP2C9酶活性,也不能诱导大鼠CYP1A2和CYP3A,同时也不是P-gp的体外抑制剂或底物。     

CYP2C19基因多态性对精神分裂症患者丙戊酸血药浓度的影响

目的 研究CYP2C19基因多态性与精神分裂症患者心境稳定剂丙戊酸血药浓度的关系。方法 选择奥氮平治疗且服用丙戊酸钠作为心境稳定剂的精神分裂症患者160例,采集血液,测定CYP2C19基因型以及丙戊酸血药浓度,比较各个基因型血药浓度的差异。结果 *2/*2型(122.06±41.30)mg·L^-1和*2/*3型(132.34±51.34)mg·L^-1患者丙戊酸血药浓度明显高于野生*1/*1型(79.41±25.14)mg·L^-1(P<0.05或P<0.01);*1/*1、*1/*2和*1/*3型之间、*2/*2和*2/*3型之间血药浓度无统计学差异;PM型血药浓度(122.13±42.85)mg·L^-1与EM型(80.59±48.60)mg·L^-1比较,显著升高(P<0.05)。 结论 *2/*2和*2/*3型CYP2C19患者,其血液丙戊酸浓度较高,该类患者服用丙戊酸作为精神分裂症心境稳定剂时,宜适当降低用药剂量。     

安徽地区CHF患者CYP3A4*?18B和CYP3A5*?3基因多态性分布及其对地高辛血药浓度的影响

摘要：目的:观察安徽地区心力衰竭（CHF）患者CYP3A4*18B和CYP3A5*3基因多态性分布情况及其对地高辛血药浓度的影响。方法:收集92例安徽地区汉族CHF患者的血液样本,进行地高辛治疗药物浓度监测（TDM）,并采用PCR-荧光探针技术检测CYP3A4*18B和CYP3A5*3基因多态性。结果:安徽地区汉族CHF患者CYP3A4*18B的3种基因型分布为*18/*18（0%）,*1/*18（0%）,*1/*1（100%）,CYP3A5*3三种基因型分布分别为*3/*3（61.9%）,*1/*3（29.4%）,*1/*1（8.7%）。CYP3A4*18B中*1/*1组的地高辛血药浓度为（1.29±0.86）μg·L-1,CYP3A5*3中*3/*3组、*1/*3组和*1/*1组对应的地高辛血药浓度分别为（1.53±0.92）μg·L-1、（1.12±0.59）μg·L-1和（0.65±0.29）μg·L-1,差异均有统计学意义（P<0.05）,而在不同性别中CYP3A4*18B和CYP3A5*3不同基因型对应的地高辛血药浓度差异无统计学意义（P>0.05）。结论:安徽地区92例CHF患者中CYP3A4*18B和CYP3A5*3基因型分别以*1/*1和*3/*3型为主,其中CYP3A5*3基因多态性可影响地高辛血药浓度。     

研析奥氮平治疗老年晚期癌症患者抑郁状态的血药浓度与临床疗效关系

目的：研析奥氮平治疗老年晚期癌症患者抑郁状态的血药浓度与临床疗效的关系，促进合理用药。方法：80例这类患者服用2.5 ~ 10 mg·d-1奥氮平，应用全自动二维液相色谱法（2D-LC/UV）检测患者用药后4周内每周奥氮平血药浓度（C奥氮平）；采用汉密尔顿抑郁量表（HAMD-24）于治疗前、治疗后4周内每周评估疗效，应用线性回归方程分析奥氮平剂量与血药浓度相关性，运用Logistic回归和受试者工作曲线（ROC）分析奥氮平血药浓度与临床疗效相关性；采用副反应量表（TESS）评估药物不良反应。结果：奥氮平日剂量（D日）和C奥氮平线性方程呈正相关（r=0.634，P<0.001）。治疗的第1、2、3、4周末，有效组与无效组患者D日、C奥氮平、HAMD-24量表减分率存在显著性差异（P<0.05）。经Logistic回归分析得出年龄大、奥氮平血药浓度低是导致奥氮平治疗效果不理想的影响因素。以C奥氮平作为疗效预测因子绘制治疗第1、2、3、4周末ROC曲线，得出约登指数最大时对应的最佳临界值切点分别11.18、13.89、11.55、12.44 ng·mL-1；未发现C奥氮平与TESS量表评分相关（P>0.05）。结论：奥氮平血药浓度与日剂量、临床疗效密切相关，治疗老年晚期癌症患者抑郁状态最低有效血药浓度范围为11~14 ng·mL-1。     

CYP2C9和VKORC1基因多态性对老年房颤患者华法林稳定剂量影响及分析

摘要：目的:探讨CYP2C9和VKORC1基因多态性对老年房颤患者华法林稳定剂量的影响,建立适合汉族人群老年房颤患者的华法林给药模型,指导华法林个体化抗凝治疗。方法:对195例口服华法林抗凝的老年患者进行CYP2C9和VKORC1基因分型,比较不同基因型房颤老年患者华法林日均稳定剂量差异。采用多重线性回归分析法依据CYP2C9和VKORC1基因型、年龄、体表面积（BSA）、胺碘酮建立华法林稳定剂量计算公式。结果:国际标准化比值（INR）稳定在2.0～3.0之间时,CYP2C9*1/*1基因型患者日均华法林剂量（3.10±0.91） mg,显著高于CYP2C9*1/*3与CYP2C9*3/*3基因型患者的（2.10±0.89） mg和（1.25±0.00） mg; VKORC1-1639AA基因型患者日均华法林剂量（2.86±0.88） mg,显著低于VKORC1-1639GA/GG基因型患者的（3.68±0.88） mg和（6.38±0.91） mg（P<0.05）。通过多元线性回归分析得出华法林稳定剂量公式,建立的回归模型中包含年龄、BSA、胺碘酮、CYP2C9和VKORC1-1639基因型,该模型能解释约60.4%个体间华法林剂量差异。结论:基于CYP2C9和VKORC1基因多态性建立的华法林稳定剂量预测公式,能帮助指导华法林在老年房颤患者中的抗凝治疗。     

复方丹参滴丸对人肝脏药物代谢酶CYP1A2活性的影响

目的:研究复方丹参滴丸对人肝脏药物代谢酶CYP1A2活性的影响,指导临床合理用药。方法:采用反相高效液相色谱法测定服用复方丹参滴丸前、后人尿液内咖啡因4种主要代谢产物的相对含量;采用(AFMU+1X+1U)/17U比率法评价人肝脏药物代谢酶CYP1A2活性的变化。结果:受试者用药前CYP1A2的平均活性为4·20±1·54,服用复方丹参滴丸14d后CYP1A2的平均活性为4·26±1·95,用药28d后CYP1A2的平均活性为4·35±1·26,二者分别比用药前升高1·42%和3·57%,但无统计学差异。结论:服用治疗剂量的复方丹参滴丸对人肝脏药物代谢酶CYP1A2的活性无明显影响,不会影响与之合用的需经CYP1A2代谢药物的疗效。     

酒石酸美托洛尔片在中国健康人体的药代动力学

目的　研究单剂量和多剂量酒石酸美托洛尔片在中国健康人体的药代动力学。方法　22名健康受试者口服酒石酸美托洛尔片50mg,用HPLC-荧光检测法测定血浆中美托洛尔的浓度。结果　所得药代动力学参数如下。单剂量:AUC0-t为(395. 6±298. 95)ng·h·mL-1,AUC0-∞为(433. 83±342. 94)ng·h·mL-1,Cmax为(63. 06±34. 61)ng·mL-1,tmax为(1. 573±0. 52)h,MRT为(7. 40±2. 31 )h;多剂量:AUCss0-t为( 504. 67±322. 35 )ng·h·mL-1,Cmax为(77. 72±45. 69)ng·mL-1,tmax为(1. 7±0. 6)h,Cmin为(4. 12±1. 57)ng·mL-1,平均稳态血药浓度Cav是( 21. 03±13. 43 )ng·mL-1,血药浓度波动度DF为(367. 29±112. 56)%。结论　酒石酸美托洛尔片单剂量和多剂量给药后,安全性良好。     

氯吡格雷对冠心病患者PCI术后CYP2C19、PON1 基因多态性与FIB、D-二聚体水平的相关性研究

目的：分析冠心病患者经皮冠状动脉介入治疗(PCI)术后,规律服用氯吡格雷治疗时CYP2C19、PON1基因多态性与血浆纤维蛋白原（FIB）、D-二聚体水平的相关性研究。方法：选取在某三甲医院确诊为冠心病且行PCI术的患者217例,对217例患者行CYP2C19*2、CYP2C19*3、CYP2C19*17、PON1基因监测,观察患者在规律服用氯吡格雷治疗（75 mg·d-1）1个月以上的血浆FIB、D-二聚体指标。结果：在217名患者中CYP2C19* 17基因未检测出突变型等位基因,因此对超快代谢型基因不做统计分析。CYP2C19基因的快代谢型、中间代谢型、慢代谢型之间的FIB指标对比均无统计学差异（P>0.05）;快代谢型与中间代谢型、快代谢性与慢代谢型之间的D-二聚体指标均无统计学差异（P>0.05）;中间代谢型与慢代谢型之间D-二聚体指标有统计学差异（P<0.05）。PON1基因GG型与GA型、GG型与AA型、GA型与AA型的FIB和D-二聚体指标水平均无统计学差异（P>0.05）。结论：携带CYP2C19慢代谢基因型的患者使用常规氯吡格雷剂量治疗,增加血栓风险,可考虑适当增加氯吡格雷服药剂量或改服替格瑞洛进行溶栓治疗。PON1基因多态性与氯吡格雷治疗血小板反应性差异并无关联性。     

氟伏沙明和CYP1A2*1F基因多态性对血清奥氮平浓度的影响

目的研究氟伏沙明与细胞色素P450酶1A2(cytochromeP4501A2,CYP1A2)基因*1F位点多态性对精神分裂症患者血清奥氮平浓度的影响。方法入组精神分裂症患者单用奥氮平者(奥氮平组)92例以及奥氮平联用氟伏沙明者(联合组)103例,采集血液,测定CYP1A2*1F基因型以及血清奥氮平浓度,比较2组以及CYP1A2*1F各个基因型间的血清奥氮平浓度差异。结果奥氮平组血清奥氮平浓度(3.39±2.70)mg·L-1·mg-1显著低于联合组(5.14±3.06)mg·L-1·mg-1(t=4.23,P=0.000)。AA型血清奥氮平浓度比CC型低[奥氮平组:(2.46±1.64)mg·L-1·mg-1 vs(4.42±2.88)mg·L-1·mg-1,P<0.05;联合组:(4.06±2.65)mg·L-1·mg-1 vs(6.86±3.25)mg·L-1·mg-1,P<0.01],但是CA型与CC型的差异无统计学显著意义。结论氟伏沙明可升高血清奥氮平浓度;不同基因型个体,血清奥氮平浓度不同;应根据氟伏沙明使用情况和CYP1A2*1F基因型个体化给药。     

羟氯喹在人肝微粒体CYP酶中的代谢研究

目的：探讨羟氯喹在人肝微粒体中的主要代谢酶及其代谢特点和参数。方法：建立高效液相色谱-荧光检测器（HPLC-FLD）测定孵育液中羟氯喹的方法,观察9种CYP酶特异性抑制剂对羟氯喹代谢的影响,计算羟氯喹的酶促动力学参数如米氏常数（Km）、最大反应速度（Vmax）和药物的内在清除率（CLint）。结果：9种酶抑制剂中孟鲁司特（CYP2CB抑制剂）、酮康唑（CYP3A4抑制剂）、噻氯匹定（CYP2B6抑制剂）能够显著抑制羟氯喹的代谢（P ＜ 0.05）。羟氯喹在人肝微粒体中Vmax为233.6 ng·mL-1·h-1·mgprotein-1,Km为14.5 ng·mL-1,CLint为16.2 h-1·mgprotein-1。结论：羟氯喹主要通过CYP2C8、CYP3A4和CYP2B6代谢,药物在体内清除速率慢,药物相互作用和蓄积是发生不良反应的重要因素。     

Relationship between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phenotype polymorphisms

Objective: The purpose of this study was to investigate whether the disposition of fluvoxamine is associated with the CYP2D6 and CYP2C19 phenotype polymorphisms. Methods: The serum concentration of fluvoxamine was followed for 48 h after oral administration of a single dose of 50 mg fluvoxamine to five poor metabolizers of the CYP2D6 test drug dextromethorphan, five poor metabolizers of the CYP2C19 test drug mephenytoin, and five extensive metabolizers of both test drugs. Results: Poor metabolizers of dextromethorphan had significantly higher areas under the serum concentration-time curve than extensive metabolizers of dextromethorphan (mean 1.31 vs 1.00 μmol · h · l⁻¹). There were no differences between poor and extensive metabolizers of mephenytoin (mean, 1.00 vs 1.15 μmol · h · l⁻¹). Conclusion: The results are consistent with a possible minor to moderate role of CYP2D6, but not CYP2C19, in fluvoxamine metabolism. Received: 25 April 1996 / Accepted in revised form: 12 November 1996     

缺血性卒中病人CYP2C19基因多态性与个体化抗血小板治疗的临床观察

目的 研究小样本缺血性卒中病人的CYP2C19基因型,根据其CYP2C19基因型指导个体化抗血小板治疗并观察其临床预后.方法 入选急性缺血卒中病人300例,对入选病人采用随机数字表法分为个体化治疗组150例和常规治疗组150例.个体化治疗组在入选后立即检测CYP2C19基因,按照不同的基因型采用个体化的抗血小板治疗方案,即快代谢型按照氯吡格雷负荷量300 mg、维持量50 mg·d-1口服;中间代谢型按照氯吡格雷负荷量300 mg、维持量75 mg·d-1口服;慢代谢型按照氯吡格雷负荷量300 mg、维持量75 mg·d-1,联合阿司匹林100 mg·d-1口服.常规治疗组直接按照氯吡格雷负荷量300 mg、维持量75 mg·d-1口服治疗,不检测CYP2C19基因.通过随访观察两组病人治疗30 d及180 d不良事件发生率之间的差异.结果 随访6个月,再发缺血性卒中的发生率在个体化治疗组显著降低(P<0.05),出血事件的发生率在个体化治疗组明显低于常规治疗组(P<0.05).结论 根据CYP2C19基因型采取不同的治疗方案可以及时发现慢代谢病人,进而调整抗血小板聚集治疗方案,降低不良事件发生率并可以减少药物的不良反应.     

The effect of perazine on the CYP2D6 and CYP2C19 phenotypes as measured by the dextromethorphan and mephenytoin tests in psychiatric patients

There is evidence that the antipsychotic drug perazine is an inhibitor of CYP2D6. This study aimed at evaluating its effect on CYP2D6 and CYP2C19 activities in submitting psychiatric patients to phenotyping with dextromethorphan and mephenytoin, respectively, substrates of these enzymes, before and during a treatment with perazine. A total of 31 patients were phenotyped with dextromethorphan (CYP2D6) and mephenytoin (CYP2C19) before and after a 2‐week treatment with 450 ± 51 mg/day (mean ± sd) perazine. At baseline, five patients appeared to be poor metabolizers (PM) of dextromethorphan and two patients of mephenytoin. The metabolic ratio (MR) of dextromethorphan/dextrorphan as determined in collected urine increased significantly (Wilcoxon; P < .0001) from baseline (0.39 ± 1.38 [mean ± sd]) till day 14 (1.46 ± 2.22). In 19 out of 26 extensive metabolizers (EM) of dextromethorphan, the phenotype changed from EM to PM. This suggests an almost complete inhibition of CYP2D6 by perazine and/or its metabolites. On the other hand, perazine (or some of its metabolites) did seemingly not inhibit CYP2C19. In conclusion, this study suggests that in patients treated with perazine and co‐medicated with CYP2D6 substrates, there could be an increased risk of adverse effects as a consequence of a pharmacokinetic interaction.     

黄芪颗粒和黄芪注射液对CYP1A2、CYP2D、CYP2C亚酶活性影响的实验研究

目的通过体内和体外实验研究黄芪颗粒和黄芪注射液对CYP1A2、CYP2D、CYP2C亚酶的活性影响。方法建立体外"cocktail"反应体系,利用LC/MS/MS法测定酶代谢产物,计算黄芪颗粒和黄芪注射液对CYP1A2、CYP2D6、CYP2C9和CYP2C19亚酶活性的影响;大鼠随机分为对照组和实验组,不同浓度黄芪颗粒和黄芪注射液连续灌胃10 d,制备肝微粒体并进行"cocktail"反应,评价两种药物体内对大鼠CYP1A2、CYP2D1、CYP2C6和CYP2C11亚酶活性影响。结果在体外"cocktail"实验中,黄芪颗粒和黄芪注射液明显地抑制了CYP2D6、CYP2C19和CYP1A2亚酶活性,而二者对于CYP2C9亚酶活性无影响。在大鼠灌胃给药实验中,黄芪颗粒在剂量32、160和800 mg.kg-1.d-1提高CYP1A2亚酶活性2.13、3.23和2.20倍,黄芪注射液在剂量0.16、0.8、4 g.kg-1.d-1提高CYP1A2亚酶活性1.65、2.26和2.89倍,而二者均未诱导CYP2D1、CYP2C6和CYP2C11亚酶活性增加。结论黄芪颗粒和黄芪注射液对CYP2D6、CYP2C19活性有抑制作用,对大鼠CYP1A2活性有诱导作用。     

基于CYP2C19基因多态性探究氯吡格雷联合依达拉奉对急性脑梗死患者神经功能的影响

目的 基于CYP2C19基因多态性探究氯吡格雷联合依达拉奉对急性脑梗死患者神经功能的影响.方法 通过真实世界研究方法,于2019年1月—2020年7月在东莞市人民医院收集氯吡格雷联合依达拉奉注射液治疗的急性脑梗死患者.采用实时荧光定量PCR法检测患者的CYP2C19基因型,根据基因型将患者分为快代谢型组、中间代谢型组和...     

Impact of CYP2A6 gene polymorphism on the pharmacokinetics of dexmedetomidine for premedication

Background: Dexmedetomidine is a widely used sedative in clinic, which is mainly metabolized by cytochrome P450 2A6 (CYP2A6). Dexmedetomidine was rarely reported for off-label usage of premedication, but lacking relevant pharmacokinetic investigations. Therefore, our study determined the dexmedetomidine pharmacokinetics of CYP2A6*4 allele in Chinese patients pretreated with dexmedetomidine whose mutation frequency of CYP2A6*4 are high, in order to provide clinical references.

Methods: Thirty-one elective surgery patients received premedication with 0.5 μg/kg dexmedetomidine via intravenous pump. Their plasma concentrations at multiple time-points and polymorphism of CYP2A6*4 were determined and statistically analyzed.

Results: 9 patients were *1/*4 or *4/*4, and 22 patients were *1/*1. The main pharmacokinetic parameters were area under curve (AUC) 1396.19 ± 332.47h· ng· l^?1, peak blood concentration (C_max) 495.50 ± 104.90ng· l^?1, distribution volume (V) 0.68 ± 0.20 L/kg, clearance (CL) 0.38 ± 0.11 L/h/kg, distribution half-life (t_1/2α) 0.05 ± 0.01h, elimination half-life (t_1/2β) 2.53 ± 0.04h. No significant pharmacokinetic differences were found among CYP2A6*1/*1, *1/*4, and *4/*4 patients.

Conclusions: In Chinese patients pretreated with dexmedetomidine, T_1/2β was consistent with that published, but T_1/2α, V and Cl were lower. It was unnecessary to consider the mutation when developing the precision regimen of dexmedetomidine.     

Comparison of enantioselective disposition of rabeprazole versus lansoprazole in renal-transplant recipients who are CYP2C19 extensive metabolizers

The purpose of this study was to investigate the comparative pharmacokinetics of rabeprazole and lansoprazole enantiomers in renal-transplant recipients on tacrolimus who were CYP2C19 extensive metabolizers. Sixteen Japanese patients were randomly assigned after renal transplantation to receive repeated doses of one of the following two regimens for 28 days; tacrolimus, mycophenolate mofetil and prednisolone together with either 20?mg of racemic rabeprazole (n?=?8) or 30?mg of racemic lansoprazole (n?=?8). The mean C_max and AUC_0–24 of (R)-lansoprazole compared to (S)-lansoprazole in renal transplant recipients were 12-fold (954?±?522 vs. 167?±?137?ng?ml^?1, respectively) and 6.9-fold (4787?±?3454 vs. 451?±?354?ng?h?ml^?1, respectively) greater, and its elimination half-life was 2.1-fold (2.3?±?1.0 vs. 1.2?±?0.6?h, respectively) longer. In contrast, although the elimination half-life of (R)-rabeprazole was significantly longer than that of the (S)-enantiomer (2.1?±?0.5 vs. 1.3?±?0.9?h, respectively; P?C_max between the (R)- and (S)-enantiomer (186?±?40 vs. 200?±?92?ng?ml^?1, respectively). In conclusion, in renal-transplant recipients who are CYP2C19 extensive metabolizers, there is less stereoselective difference in the pharmacokinetic disposition between the (R)- and (S)-enantiomers of rabeprazole than those of lansoprazole.