CYP2C9抑制剂对艾瑞昔布大鼠体内药动学的影响

目的：考察CYP2C9抑制剂胺碘酮对艾瑞昔布在大鼠体内药动学的影响。方法： 40只健康雄性SD大鼠随机分为2组（n=20）,实验组连续7 d灌胃胺碘酮灌胃液（40 mg·kg^-1,qd）,对照组灌胃等量空白灌胃液。2组均于第8天单次灌胃艾瑞昔布灌胃液20 mg·kg^-1,按确定时间点取血,LC-MS/MS法测定艾瑞昔布血药浓度,DAS 2.1.1软件拟合药时曲线并计算药动学参数,SPSS 13.0软件进行统计学分析。结果：实验组和对照组的主要药动学参数如下：AUC_{0-24 h}分别为（1 814.8±693.4） ng·h·mL^-1和（1 125.1±457.6） ng·h·mL^-1;AUC_0-∞分别为（2 091.6±887.1） ng·h·mL^-1和（1 331.3±592.6） ng·h·mL^-1;t_1/2分别为（7.8±4.5） h和（7.4±3.8） h;t_max分别为（1.7±0.6） h和（1.46±0.60） h;CL分别为（0.01±0.01） L·h^-1·kg^-1和（0.02±0.01） L·h^-1·kg^-1;V分别为（0.11±0.05） L·kg^-1和（0.17±0.07） L·kg^-1;C_max分别为（268.2±115.7） ng·mL^-1和（162.2±53.0） ng·mL^-1。与对照组相比,实验组大鼠的AUC_{0-24 h}、AUC_0-∞、C_max显著增大（P<0.05）,V、CL显著减小（P<0.05）,其他参数差异无统计学意义（P>0.05）。结论： CYP2C9抑制剂（胺碘酮）对艾瑞昔布在大鼠体内的药动学产生影响。     

中国人群CYP2D6基因多态性对美托洛尔药代动力学的影响

目的：研究中国人群CYP2D6基因多态性对美托洛尔药代动力学的影响。方法：使用基因芯片技术测定中国健康志愿者CYP2D6的基因型,按照分型结果将志愿者分为四组,第1组：CYP2D6＊2W＊10W,第2组：CYP2D6＊2H＊10W或CYP2D6＊2M＊10W,第3组：CYP2D6＊2M＊10H,第4组：CYP2D6＊2M＊10M,每组筛选10人,共40人。各组志愿者单次口服100mg美托洛尔后,使用HPLC方法测定血和尿中美托洛尔及其代谢产物α-羟基美托洛尔（HM）的浓度,研究其在不同基因型志愿者体内的药代过程。结果：第2组美托洛尔及其HM的主要药动学参数与第1组相比均没有统计学差异。第3组美托洛尔的t1/2、AUC、Cmax显著高于第1组（P〈0.05）;而HM的t1/2延长47.3%,AUC降低56.0%（P〈0.05）。第4组美托洛尔的t1/2、AUC、Cmax均显著高于第1组（P〈0.05）和第3组（P〈0.05）;HM的t1/2、AUC、Cmax与第1组和第3组相比均有统计学差异（P〈0.05）,且呈现基因剂量效应。第3组和第4组的口服清除率和肾清除率均低于第1组,而0-24h代谢比率分别为第1组的1.82倍和3.96倍。结论：CYP2D6＊2对于美托洛尔的药代动力学过程没有影响;但CYP2D6＊10可降低酶活性,且CYP2D6＊10纯合子变异比杂合子变异对美托洛尔药代动力学的影响更大,呈现基因剂量效应。     

艾瑞昔布片在中度肝功能不全受试者的药代动力学研究

目的 通过比较艾瑞昔布及代谢产物在肝功能不全和健康受试者的药代动力学特征,为制订艾瑞昔布在肝功能不全患者的临床给药方案提供参考.方法 采用1:1平行开放对照试验设计,入选肝功能Child-Pugh B级的受试者10例,设为A组;然后根据A组受试者的年龄、性别、体重特征匹配相应的健康受试者作为平行对照的B组.2组受试者于...     

艾瑞昔布对CYP2C9酶活性及mRNA和蛋白表达的影响

目的:评价艾瑞昔布对CYP2C9酶活性及mRNA和蛋白表达的影响。方法:采用超高效液相色谱(UPLC),色谱柱：Acquity UPLC BEH-C₁₈柱(2.1 mm×50 mm, 1.7μm);流动相为水-乙腈(76∶24,V/V);流速0.4 mL·min^-1;检测波长235 nm;柱温30℃;进样量2μL;内标为卡马西平。选择甲苯磺丁脲为CYP2C9酶特异性探针药物,与艾瑞昔布在肝微粒体中共同孵育,UPLC测定代谢产物4-羟基甲苯磺丁脲的生成量,考察艾瑞昔布对CYP2C9酶活性的影响。Wistar大鼠给予艾瑞昔布,RT-PCR和Western Blot测定肝组织中CYP2C9酶活性及mRNA和蛋白表达。结果:随着艾瑞昔布浓度的升高,肝微粒体孵育体系中4-羟基甲苯磺丁脲生成量降低,艾瑞昔布对CYP2C9活性呈剂量依赖性抑制作用,IC₅₀值为74.77μmol·L^-1;随着给药时间延长,大鼠肝脏CYP2C9酶的mRNA和蛋白表达减少(P<0.05)。结论:艾瑞昔布可降低CYP2C9酶的mR...     

艾瑞昔布的药物动力学研究

本实验对新药艾瑞昔布进行健康人体药代动力学研究。研究结果表明,艾瑞昔布在人体内发生较强的首过代谢,主要生成羟基代谢产物M1和羧基代谢产物M2。饮食影响的药动学研究表明,餐后给药能显著提高艾瑞昔布的生物利用度。建议餐后给药。     

CYP2D6遗传多态性对临床个体化给药的影响

本文总结了经CYP2D6代谢的临床常用药物,并对此类药物实现临床个体化给药的方法进行了探讨。同时介绍了CYP2D6的各种表型及其在不同种族之间的分布情况,以及该分布对制定临床给药方案的影响。     

帕罗西汀片健康人体生物等效性研究及CYP2D6基因多态性对其药代动力学的影响

目的 研究帕罗西汀片仿制药和原研药在中国健康受试者中的生物等效性及安全性,并探讨CYP2D6基因多态性对帕罗西汀体内药代动力学（PK）参数的影响。方法 按单中心、随机、开放、单次给药、两序列、两周期、双交叉设计,共入组26例中国健康成年受试者,在空腹条件下每周期分别单次口服帕罗西汀片的受试制剂或参比制剂20 mg。采用经确证的高效液相色谱-质谱联用法测定血浆帕罗西汀浓度,使用WinNonlin软件按非房室模型计算PK参数,并评价其生物等效性;同时测定受试者CYP2D6各单核苷酸多态性位点的基因型,并进行代谢表型活性评分,比较不同评分受试者PK参数的差异。结果 受试制剂及参比制剂的主要PK参数如下：C_max分别为（5.28±3.71）和（5.74±4.70）ng·mL^-1,T_max分别为（5.12±1.63）和（4.69±1.52）h, AUC_0-t分别为（109.02±101.29）和（113.26±111.32）ng·mL·h^-1,AUC_0-∞分别为（1...     

氧化苦参碱对大鼠CYP2D6酶的影响

目的 通过氧化苦参碱的大鼠体内、外实验,观察氧化苦参碱对大鼠CYP2D6 亚型酶的影响.方法 HPLC法测定大鼠尿液及肝微粒体中探针药物右美沙芬(DM)、代谢物去甲右美沙芬(DT)的含量.对照组和氧化苦参碱组大鼠分别经口给予生理盐水和氧化苦参碱两周,HPLC法测定大鼠尿样及肝微粒体中CYP2D6的探针药物右美沙芬的代谢率,观察氧化苦参碱对CYP2D6活性的影响.并且通过特异性抑制剂确定在肝微粒体重组系统中氧化苦参碱对CYP2D6亚型的影响.结果 实验组大鼠给予氧化苦参碱(100mg/kg),其尿样中右美沙芬的代谢率与对照组相比没有明显差别(P>0.05);实验组大鼠肝微粒体中加入右美沙芬(0.324mmol/L),其右美沙芬的代谢率与对照组相比没有明显差别(P>0.05);氧化苦参碱没有明显降低右美沙芬的代谢率(P>0.05),而CYP2D6特异性抑制剂西米替丁却明显降低右美沙芬的代谢率(P<0.01).结论 氧化苦参碱对CYP2D6酶无明显影响.     

血塞通注射液对大鼠体内CYP2D1的影响

目的:研究血塞通注射液连续多次给药后对大鼠CYP2D1酶的影响。方法:12只大鼠采用自身对照的实验方法,先后单用探针药物(氢溴酸右美沙芬10mg.kg-1)以及合用血塞通注射液(180mg.kg-1)7d,采用HPLC法测定血浆中右美沙芬的浓度,观察血塞通注射液对大鼠CYP2D1酶的影响。结果:右美沙芬单用以及与血塞通注射液合用的主要药动学参数分别为t1/2β(153.1±25.4)min,(179.5±48.6)min(P<0.05);AUC0→t(85.6±9.9)mg.L-1.min,(105.2±21.2)mg.L-1.min(P<0.01),CL(0.098±0.012)mL.kg-1.min-1,(0.080±0.016)mL.kg-1.min-1(P<0.01)。结论:血塞通注射液对大鼠CYP2D1酶有明显抑制作用。     

冰片对大鼠体内CYP2D诱导作用研究

冰片是传统中药,近年来许多文献报道冰片能提高其他药物的生物利用度,促进其他药物进入血脑屏障,因而冰片与其他药物合用可能产生的药物相互作用受到高度重视,但冰片对肝脏细胞色素P450酶的影响却鲜有报道。本文研究了雄性Wistar大鼠连续灌胃冰片一周对大鼠肝脏CYP2D表达与活性以及对CYP2D探针底物右美沙芬大鼠体内药代动力学的影响。结果表明,冰片(33、100和300 mg·kg-1·d-1)给药一周对大鼠肝脏CYP2D1 m RNA和蛋白表达无明显影响,但却显著诱导了CYP2D活性(P<0.05),分别达到1.71、1.97和2.89倍。此外,与对照组相比,冰片(300 mg·kg-1·d-1)预给药一周组右美沙芬的达峰浓度Cmax降低了10.6%(P>0.05),曲线下面积AUC0-∞减少了27.5%(P<0.01),清除率CL/F增大了41.1%(P<0.01),表观分布容积Vz/F增大了23.1%(P>0.05),表明冰片预给药一周能明显加速CYP2D探针底物右美沙芬的体内清除。由于冰片对大鼠肝脏CYP2D活性的诱导作用,提示当冰片与CYP2D底物药物共用时,可能存在发生代谢性相互作用的风险。     

CYP2D6 and CYP2C19 genotypes in an elderly Swedish population

Objective: Eighty-three healthy elderly Swedish subjects (age 87 ± 4 years, mean ± SD, range 80–98 years) were genotyped with respect to the two genetic polymorphisms of oxidative drug metabolism, CYP2D6 and CYP2C19, using allele-specific polymerase chain reaction (PCR). A control population consisted of 248 younger unrelated healthy volunteers (age 31 ± 9 years, range 19–63 years) for CYP2D6, and 162 (age 30 ± 8 years, range 19–55 years) for CYP2C19. Results: No significant differences were found between the control groups and the elderly subjects with respect to the frequencies of the defect alleles CYP2D6*3, CYP2D6*4, CYP2C19*2 and CYP2C19*3. Neither were there any differences in the genotype frequencies, or the predicted phenotype frequencies. The study indicates that the CYP2D6 and CYP2C19 genotypes play no major role in the probability of reaching high age. Conclusion: No genetically determined differences in the pharmacokinetics of drugs metabolized by these two polymorphic enzymes are to be expected in the oldest age groups compared with younger adults. Received: 10 March 1998 / Accepted: 1 May 1998     

细胞色素P4502D6基因多态性和药物相互作用

细胞色素P4502D6（CYP2D6）是一种重要的P450系氧化代谢酶,参与多种重要药物的代谢.CYP2D6具有基因多态性,对药物的代谢呈现明显的个体差异.而且CYP2D6能被多种药物竞争性抑制和诱导,药物联用时易产生相互作用.本文从CYP2D6的基因多态性与代谢表型、底物竞争作用、代谢酶的诱导和抑制等方面,探讨CYP2D6基因多态性与药物相互作用的关系.     

注射用灯盏花素对大鼠CYP2D6体内代谢活性的影响

目的:研究灯盏花素对大鼠细胞色素P4502D6(CYP2D6)体内代谢活性的影响。方法:试验分为3组,即对照(生理盐水)和灯盏花素高、低剂量(0.54、0.18mg·100g-1)组,静脉注射给药,每天1次,连续14d。各组分别于第15天注射美托洛尔溶液,于给药前和给药后不同时间点眼内眦静脉取血0.8mL,使用高效液相色谱法测定血浆中美托洛尔的浓度。结果:静脉给予大鼠注射用灯盏花素14d后,灯盏花素高剂量组美托洛尔的AUC和t1/2显著高于对照组,CL显著低于对照组(P<0.05)。灯盏花素低剂量组虽然也有相同趋势,但无显著性差异。结论:高剂量注射用灯盏花素可显著抑制大鼠CYP2D6的体内活性。     

Influence of donor and recipient genotypes on CYP2D6 phenotype after liver transplantation: a study of mutations CYP2D6*3 and CYP2D6*4

Objective: After liver transplantation (LT), genotypic differences between the recipient and the transplanted liver, medications and post-LT complications may all affect drug metabolism. We have studied the effect of two CYP2D6 mutations in the donor and the recipient on post-LT CYP2D6 phenotype. Method: The CYP2D6 phenotype was assessed in 48 patients before and after LT with debrisoquine or␣dextromethorphan. CYP2D6*3 (CYP2D6A) and CYP2D6*4 (CYP2D6B) mutations were detected in the donor and the recipient using polymerase chain reaction. Results: Before LT, 40 subjects were classified as extensive metabolisers (EM) and 8 as poor metabolisers (PM); after transplantation, 41 were EMs and 7 were PMs. Genotype and phenotype were in agreement in 100% of EMs and 40% of PMs. The low percentage of agreement in PMs could not be explained by severely altered liver function. The phenotype of 13 subjects was apparently changed by LT: 6 EMs became PMs and 7 PMs became EMs. All four subjects in whom genotype changed following LT had a corresponding change in phenotype: two EM subjects became PMs and two PM subjects became EMs. Conclusion: The low percentage of agreement in PMs may be partly explained by mutations other than CYP2D6*3 and CYP2D6*4. Nevertheless, our study shows that the CYP2D6 genotype of the donor controls the phenotype of the recipient of a liver transplantation. Received: 2 June 1997 / Accepted in revised form: 9 October 1997     

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.     

奥扎格雷钠对大鼠CYP2D6亚型酶的影响

目的通过奥扎格雷钠的大鼠体内、外实验,观察奥扎格雷钠对大鼠CYP2D6亚型酶的影响。方法对照组和奥扎格雷钠诱导组大鼠分别经口给予生理盐水和奥扎格雷钠1wk,HPLC法测定大鼠尿样及肝微粒体中CYP2D6的探针药物右美沙芬的代谢率,观察奥扎格雷钠对CYP2D6活性的影响。结果①大鼠给予奥扎格雷钠(37mg·kg-1),其尿样中右美沙芬的代谢率明显高于对照组(P<0·01);②奥扎格雷钠诱导组大鼠肝微粒体中加入右美沙芬(0·324mmol·L-1),其右美沙芬的代谢率明显高于对照组(P<0·01);③奥扎格雷钠与CYP2D6特异性抑制剂西米替丁可明显降低右美沙芬的代谢率(P<0·01),并且奥扎格雷钠组其右美沙芬的代谢率低于西米替丁组(P<0·05);④奥扎格雷钠IC50=26·5μmol·L-1,西咪替丁IC50=86·3μmol·L-1,奥扎格雷钠诱导组肝微粒体Km=0·67mmol·L-1,Vmax=2·13nmol·min-1·g-1protein;对照组肝微粒体Km=0·29mmol·L-1,Vmax=0·91nmol·min-1·g-1protein;⑤体内和体外相应实验数据具有很好的相关性(r=0·9811)。结论奥扎格雷钠可诱导CYP2D6酶的活性。     

Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes

AIMS: To determine the frequencies of 11 CYP2D6 mutant alleles (CYP2D6*2, *3, *4, *5, *8, *10, *11, *12, *14, *17 and *18), and their relation to the metabolic capacity of CYP2D6 in Japanese subjects. METHODS: One hundred and sixty-two unrelated healthy Japanese subjects were genotyped with the polymerase chain reaction amplification method and 35 subjects were phenotyped with dextromethorphan. RESULTS: The frequencies of CYP2D6*2,*5, *10 and *14 were 12.9, 6.2, 38.6 and 2.2% in our Japanese subjects, respectively. CYP2D6*3, *4, *8, *11, *12, *17 and *18 were not detected. The mean log metabolic ratio of dextromethorphan in subjects with genotypes predicting intermediate metabolizers was significantly greater than that of heterozygotes for functional and defective alleles. CONCLUSIONS: CYP2D6*5 and CYP2D6*14 are the major defective alleles found in Japanese subjects. In addition, CYP2D6*10 may play a more important role than previously thought for the treatment of Japanese patients with drugs metabolized by CYP2D6.     

The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population

Objective: The cytochrome P ₄₅₀ isozymes CYP2D6 and CYP2C19 exhibit genetic polymorphism in human, including a marked interethnic difference. As the functional status of the isozymes CYP2D6 and CYP2C19 have an impact on the pharmacokinetics of some antidepressants, we investigated whether the disposition of venlafaxine was affected by the CYP2D6 and CYP2C19 genotypes. Methods: Twenty-eight adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotype was determined using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analysis and XbaI-RFLP analysis. Subjects were categorized into the following four groups: group 1 CYP2D6*10/*10; group 2 CYP2D6*1/*10 and *2/*10; group 3 CYP2D6*1/*1, *1/*2 and *2/*2; and group 4 the other genotypes. Two defective CYP2C19 alleles (CYP2C19*2 and CYP2C19*3) were identified by means of PCR-RFLP analysis. Venlafaxine was administered orally following an overnight fast. Plasma concentrations of venlafaxine and O-desmethylvenlafaxine were monitored using high-performance liquid chromatography up to 24 h. Results: The peak plasma concentration and values of area under the concentration–time curve up to 24 h for venlafaxine were 298% and 453% higher for group 1 than group 3, and 91% and 120% higher for group 2 than for group 3, respectively. The homozygote for two defective alleles of CYP2C19 showed a higher concentration of venlafaxine within group 1 and group 2. Conclusion: The CYP2D6*10 allele and two CYP2C19 defective alleles, common in an Asian population, are the most likely genetic factors to use in determining interindividual differences in the pharmacokinetics of venlafaxine, although the results with respect to CYP2C19 are preliminary because of the few subjects used. Received: 6 July 1999 / Accepted in revised form 11 January 2000     

The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver

AIMS: To investigate in a large panel of 50 human liver samples the contribution of CYP2C9, CYP2D6, and CYP3A4 to the overall formation of the potent antioestrogen Z-4-hydroxy-tamoxifen, and how various genotypes affect its formation from tamoxifen. METHODS: The formation of Z-4-hydroxy-tamoxifen from 10 microm tamoxifen was studied in human liver microsomes (n=50), characterized for CYP2B6, CYP2C9, CYP2D6 and CYP3A4 expression, and CYP2B6, CYP2C9 and CYP2D6 genotype. The effect of chemical and monoclonal antibody inhibitors, and the formation in supersomes expressing recombinant CYP isoforms was also investigated. Z-4-hydroxy-tamoxifen was quantified using LC-MS analysis. RESULTS: Z-4-hydroxy-tamoxifen was formed by supersomes expressing CYP2B6, CYP2C9, CYP2C19 and CYP2D6, but not CYP3A4. In agreement with these data, the mean formation of Z-4-hydroxy-tamoxifen was inhibited 49% by sulphaphenazole (P=0.001), 38% by quinidine (P<0.05) and 13% by monoclonal antibody against CYP2B6 (MAB-2B6, P<0.05). Furthermore, Z-4-hydroxy-tamoxifen formation significantly correlated with both CYP2C9 expression (r(s)=0.256, P<0.05) and CYP2D6 expression (r(s)=0.309, P<0.05). Genotypes of CYP2D6, CYP2B6 and CYP2C9 had an effect on metabolite formation in such a way that samples with two nonfunctional CYP2D6, or two variant CYP2C9 or CYP2B6 alleles, showed lower enzyme activity compared with those with two functional or wild-type alleles, (5.0 vs 9.9 pmol mg(-1) protein min(-1), P=0.046, 5.1 vs 9.9 pmol mg(-1) protein min(-1), P=0.053, and 6.8 vs 9.4 pmol mg(-1) protein min(-1), P=0.054, respectively). CYP2D6 and CYP2C9 contribute on average 45 and 46%, respectively, to the overall formation of Z-4-hydroxy-tamoxifen. CONCLUSIONS: CYP2B6, CYP2C9 and CYP2D6 genotypes all affected Z-4-hydroxy-tamoxifen formation and can predict individual ability to catalyse this reaction.