刘昭前
药理学
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- 姓名:刘昭前
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博士生导师
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学科领域:
药物化学
- 研究兴趣:药理学
刘昭前,男,1963年8月出生,中共党员,博士,教授,硕士研究生导师,遗传药理学研究室副主任。一直从事药理学的教学和科研工作,已成为本学科的专业骨干和学科带头人。到目前为止,共发表论文40篇,其中单独或与其他人合作在国际动脉粥样硬化杂志、美国药理学和实验治疗学杂志、英国临床药理学杂志、中国药理学报等杂志上发表SCI论文20篇,SCI引用19篇,被SCI期刊引用104次。作为第一负责人,2000年获国家自然科学基金资助项目一项(15万元),2001年被评为湖南省普通高等学校青年骨干教师培养对象,2002年获教育部“高校优秀青年教师资助计划(10万元)”奖,2004年入选“教育部新世纪优秀人才支持计划”(50万元)奖和湖南新世纪121人才工程;同时作为课题组主要成员之一,2001年获国家自然科学基金重点项目资助(145万元)和美国CMB资助(30万美元)。获省部级科技成果奖5项,参编教材和专著3部,现为《中南药学》杂志编委,湖南省医学会临床药理学专业委员会委员兼秘书,湖南省高新技术产业发展委员会生物医药领域评审专家,湖南省新药评审专家。 1980年7月--1985年7月,湖南医科大学,获学士学位; 1985年7月--1990年7月, 湖南医科大学药理教研室,助教; 1990年7月--1993年7月,湖南医科大学攻读硕士研究生,获医学硕士学位; 1993年7月一1996年11月, 湖南医科大学基础与临床药理研究所,讲师; 1996年11月--1997年12月, 德国慕尼黑大学,访问学者; 1997年12月--2001年7月,湖南医科大学基础与临床药理研究所,获医学博士学位,副教授; 2001年7月一2002年8月, 中南大学临床药理研究所,副主任,副教授; 2002 年8月一2004 年8月, 美国印第安那大学医学院,博士后; 2004 年8月一现在 中南大学临床药理研究所,副主任,教授.
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【期刊论文】The distribution and gender difference of CYP3A activity in Chinese subjects
刘昭前, Bing Zhu, Zhao-Qian Liu, Guo-Lin Chen, Xiao-Ping Chen, Dong-Sheng Ou-Yang, Lian-Sheng Wang, Song-Lin Huang, Zhi-Rong Tan & Hong-Hao Zhou
2003 Blackwell Publishing Ltd Br J Clin Pharmacol55, 264-269,-0001,():
-1年11月30日
Aims To investigate the distribution of CYP3A activity in the Chinese population, and to test for gender-related differences in CYP3A activity. Methods Using midazolam as a probe drug, CYP3A activity in 202 Chinese healthy subjects (104 men) was measured by plasma 1-hydroxymidazolam: midazolam (1-OH-MDZ: MDZ) ratio at 1 h after oral administration of 7.5mg midazolam. The different phases of the menstrual cycle including preovulatory, ovulatory and luteal phases of 66 women phenotyped with midazolam were recorded. The concentrations of 1-OH-MDZ and MDZ in plasma were measured by HPLC Results A 13-fold variation of CYP3A activity (log1-OH-MDZ: MDZ: range-0.949-0.203) was shown. The CYP3A activity was normally distributed as indicated by the frequency distribution histogram, the probit plot and the Kolmogorov-Smirnov test (P>0.05). The CYP3A activity of women was higher than that of men (median: -0.36vs-0.43, P<0.05; 95% CI for difference: -0.127,-0.012). There was a significant difference in CYP3A activity between the three phases of the menstrual cycle. The activity was highest in the preovulatory phase and decreased sequentially in the ovulatory and luteal phases (P<0.05). Conclusions A normal distribution of CYP3A activity was observed in the Chinese population. The CYP3A activity is higher in female subjects than in males. CYP3A activity differed across the phases of the menstrual cycle.
CYP3A, gender, menstrual cycle, midazolam
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【期刊论文】反相高效液相色谱法测定体外人肝微粒体中氟西汀及其代谢产物去甲氟西汀1
刘昭前, 程泽能, 王伟, 谭志荣, 欧阳冬生, 周宏灏
ISSN0253-9756 Acta PharmacolSin 2000 Nov; 21 (11): 1027-1030,-0001,():
-1年11月30日
目的:建立同时测定体外肝微粒体中氟西汀及其代谓十产物去甲氟西汀的反相高效液相色谱紫外检测法。方法:含微粒体蛋白和NADPH发生系统及氟西汀的孵育液加入冰乙腈酸终止反应后,再加入去甲替林作为内标并以,z.正己烷和乙腈的混合液进行萃取,然后以反相ODS柱分离,在226nlTl处以紫外检测器进行检测。结果:孵育体系中没有明显的干扰峰出现,氟西汀和去甲氟西汀洗脱快,分离好,线性范围均为10-800ug/L,最低检测限均为5ug/L,相对回收率为94%-104%,变异系数少于9.1%。结论:本法快速,灵敏,回收率高,且萃取过程简单,可用于体外氟西汀的代谢研究。
氟西汀, 高压液相色谱法, 肝微粒体
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刘昭前, LIU Zhao-Qian, SHU Yah, HUANG Song-Lin, WANG Lian-Sheng, HE Nan, ZHOU Hong-Hao
IsN0253-9756 ActaPhanngacol Sin 2001 Jan; 22 (1): 85-90,-0001,():
-1年11月30日
AIM: The present study was designed to define the ki-netic behavior of fluoxetine N-demethylation in human liver microsomes and to identify the isoforms of cy-tochrome P-450 (CYP) involved in this metabolic path-way. METHODS: The kinetics of the formation ofnorfluoxetine was determined in human liver microsomes from six genotyped CYP2C19 extensive metabolizers (EM). The correlation studies between the fluoxetine N-demethylase activity and various CYP enzyme activi-ties were performed. Selective inhibitors or chemical probes of various cytochrome P-450 isoforms were also employed. RESULTS: The kinetics of norfluoxetine formation in all liver microsomes were fitted by a single- enzyme Michaelis-Menten equation (mean Km=32umol/L-7umol/L). Significant correlations were found between N-demethylation of fluoxetine at both 25/anol/L and 100 p.mol/L and 3-hydroxylation of tolbu- tamide at 250 panol/L (rl=0.821, P1=0.001; r2=0.668, P2=0.013), respectively, and S-mephenytoin 4'-hydroxylase activity (r=0.717, P=0.006) at high substrate concentration of 100/zmol/L. S-mephenytoin (SMP)(a CC19 substrate) at high concentration and sulfaphenazole (SUL)(a selective inhibitor of CYP2C9) substantially inhibited norfluoxetine formation. The re-action was minimally inhibited by coincubation with chemical probe, inhibitor of CYP3A4 (tfiacetylolean-domycin, TAO). The inhibition of fluoxetine N-demethylation at high substrate concentration (100ptmoL/L) was greater in PM livers than in EM livers (73% vs4, 5%, P<0.01) when the microsomes were precoincu-bated with SUL plus TAO. CONCLUSION: Cy-tochrome P-450 CYP2C9 is likely to be a major CYP iso-form catalyzing fluoxetine N-demethylation in human liv-er microsomes at a substrate concentration close to the therapeutic level, while polymorphic CYP'2C19 may play a more important role in this metabolic pathway at highsubstrate concentration.
fluoxetine, pharmacokinetics, liver microsomes, cytochrome P-450 CYP2C19, cytochrome
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【期刊论文】CYP2C19genotype and S-mephenytoin 4
刘昭前, Nan He
EurJ Clin Pharmacol (2002) 58: 15-18,-0001,():
-1年11月30日
Aims: To investigate the incidence of the CYP2C19 polymorphism in the Chinese Dai population. Methods: One hundred and ninety-three healthy Chinese Dai volunteers were identified with respect to CYP2C19 by genotype and phenotype analyses. A polymerase chain reaction-restriction fragment length polymorphism method was performed for genotyping procedures. The 4-hydroxymephenytoin (4-OH-MP) and S/R-mephenytoin (S/R-MP) excreted in the urine were determined by high-performance liquid chromatographyand gas chromatography, respectively. Results: Eighteen subjects were identified as poor metabolisers (PMs). The frequency of PMs in the Chinese Dai subjects was 9.3% (95% confidence interval 5.2, 13.4), which is lowerthan that in the Chinese Han population (P<0.05). Chinese Dai subjects had a higher frequency of the mutant CYP2C19*2 allele (0.303) and a lowerfr equency of the mutant CYP2C19*3 allele (0.034). These two mutant alleles could explain all defi-ciencies of CYP2C19 activity in the Chinese Dai subjects. The frequency of the CYP2C193 allele is significantly lowerthan that in the Chinese Han population (P<0.05). The mean S/R ratio was lower in the homozygous extensive metabolisers (EMs) compared with that in heterozygous EMs (P<0.01), and the latter was lowerthan that in the PMs (P<0.01). Furthermore, the mean S/R ratio in CYP2C193/CYP2C192 heterozygous PMs was possibly lower than that in the CYP2C192/CYP2C19*2 homozygous PMs (P<0.05). Conclusion: The frequencies of PMs and CYP2C19*3 allele in the Chinese Dai population are significantly lowerthan those in the Han population. The CYP2C19genotype analysis is largely consistent with the mephenytoin phenotype analysis. The variability of S/R ratios in EMs and PMs shows a gene-dosage e ect.
S-mephenytoin, Genetic polymorphism, S/, R ratio
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刘昭前
,-0001,():
-1年11月30日
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【期刊论文】Effect of the CYP2C19 oxidation polymorphism on
刘昭前, Zhao-Qian Liu, Ze-Neng Cheng, Song-Lin Huang, Xiao-Ping Chen, Dong-Sheng Ou-Yang, Chang-Hong Jiang and Hong-Hao Zhou
2001 Blackwell Science Ltd Br J Clin Pharmacol, 52, 96-99,-0001,():
-1年11月30日
Aims The study was designed to investigate whether genetically determined CYP2C19 activity affects the metabolism of fluoxetine in healthy subjects. Methods A single oral dose of fluoxetine (40mg) was administrated successively to 14 healthy young men with high (extensive metabolizers, n=8) and low (poor metabolizers, n=6) CYP2C19 activity. Blood samples were collected for 5
CYP2C19, fluoxetine, gene dose, genotype, norouoxetine, pharmacokinetics
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【期刊论文】Ethnic Differences in Drug Metabolism
刘昭前, Hong-Hao Zhou and Zhao-Qian Liu
,-0001,():
-1年11月30日
Ethnic differences in drug metabolism are well documented for a number of drugs. The molecular mechanisms responsible for ethnic differences in drug metabolism have been partly clarified because of the advances in molecular biology in recent years. Gene dosage determines the drug metabolism as demonstrated for S-mephenytoin and diazepam metabolism. Genotype analysis indicates a different frequency for the mutant alleles in different ethnic populations, which results in variations in the frequency of subjects who are homozygous for the mutant allele among the extensive metabolizers in different ethnic populations. Ethnic differences in drug metabolism may result from differences in distribution of a polymorphic trait and mutations which code for enzymes with abnormal activity which occur with altered frequency in different ethnic groups.
Ethnic differences, Genetics polymorphism, CYP2D6, CYP2C19, Drug metabolism, Pharmacogenetics, Gene dosage effect.,
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刘昭前, Zhao-Qian Liu, Zhi-Rong Tan, Dan Wang, Song-Lin Huang, Lian-Sheng Wang, Hong-Hao Zhou
Journal of Chromatography B, 769(2002)305-311 ,-0001,():
-1年11月30日
An gas chromatography-electron-capture detection method has been developed for simultaneous determination of fluoxetine and p-trifluoromethylphenol (TFMP), an O-dealkylated metabolite of fluoxetine in human liver microsomes. Prior to the analysis, aliquots of alkalinized microsomal mixture were extracted with ethyl acetate solvent containing acetonitrile (10%, v/v) and the derivatizing reagent, pentafluorobenzenesulfonyl chloride (0.1%, v/v). The organ phase was retained and taken to dryness, the residue was reconstituted in methanol, and the aliquot of extracts was injected directly into a gas chromatograph equipped with an electron-capture detector. 2, 4 Dichlorophenol was added to the initial incubation mixture and carried through the procedure as the internal standard. The method provided the mean recoveries of up to 103% for fluoxetine and 104% for TFMP. Acceptable relative standard deviations were found for both within-run and day-to-day assays. The practical limit of detection (signal-to-noise ratio53) was 1.62ng/ml for TFMP and 6.92ng/ml for fluoxetine in human liver microsomes, and the limit of quantitation was 8.1 pg for TFMP and 34.6 pg for fluoxetine. The assay is rapid and sensitive and has been applied successfully to simultaneous quantification of fluoxetine and TFMP in human liver microsomes with different CYP2C19 genotypes.
Fluoxetine, p-Trifluoromethylphenol
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刘昭前, Jie Liu, MD, Zhao-Qian Liu, PhD, Zhi-Rong Tan, BS, Xiao-Ping Chen, MS, Lian-Sheng Wang, Gan Zhou, and Hong-Hao Zhou, MD Changsha, Hunan, China
CLINICAL PHARMACOLOGY & THERAPEUTICS OCTOBER 2003,-0001,():
-1年11月30日
Objectives: Our objectives were to determine whether the Gly389 polymorphism of the β1-adrenergic receptor exhibits reduced responsiveness in vivo and to test the hypothesis that the Gly389Arg polymorphism affects the blood pressure and heart rate response to metoprolol. Methods: β1-Adrenergic receptor genotype was determined by polymerase chain reaction-restriction fragment length polymorphism assay. Exercise-induced heart rate increases were compared to determine the functional significance in vivo in 8 healthy Chinese men homozygous for Gly389 and 8 homozygous for Arg389. All of the subjects were given 25, 50, or 75mg of metoprolol every 8 hours; the dosages were given in a random order, and each dosage was given for β1 day. The degree of β-blockade was measured as the reduction in resting and exercise heart rates and blood pressures. Plasma metoprolol concentrations were measured by the use of HPLC-fluorescence detection. Results: Exercise led to a workload-dependent increase in heart rate. There were no differences in exerciseinduced heart rate increases between Arg389 and Gly389 homozygotes. Oral metoprolol caused significant dose-dependent decreases in both resting and exercise heart rates in both groups. The reductions in the resting heart rate in 3 dosage levels of metoprolol were 6.3%±0.8% versus 4.1% 0.7%, 10.1%±1.0% versus 6.2%±1.1%, and 14.4%±1.4% versus 10.9%±1.3% in homozygous Arg389 subjects and Gly389 subjects, respectively (P=.008). We also found differences with respect to the exercise heart rate (8.9%±0.5%, 14.0%±0.9%, and 20.1%±1.5% in Arg389 subjects and 6.6%±0.7%, 11.7%±1.0%, and 16.4%±1.3% in Gly389 subjects; P=.017) and systolic pressure (5.9%±0.7%, 9.2%±1.0%, and 11.6% 1.2% in Arg389 subjects and 4.6%±0.5%, 6.0%±0.8%, and 9.9%±0.9% in Gly389 subjects; P=.011). However, the difference in the fall in diastolic pressure was not statistically significant (P=.442).
The Arg389 variant of the β1-adrenergic receptor was associated with a greater response to metoprolol than that of Gly389 in young,, male Chinese subjects., These data suggested that the β1-adrenergic receptor Gly389Arg polymorphism is of major functional importance in vivo.,
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刘昭前, ZHAO-QIAN LIU, BING ZHU, YUN-FU TAN, ZHI-RONG TAN, LIAN-SHENG WANG, SONG-LIN HUANG, YAN SHU, and HONG-HAO ZHOU
JPET 299: 105-111, 2001,-0001,():
-1年11月30日
This work evaluated the kinetic behavior of fluoxetine O-dealkylation in human liver microsomes from different CYP2C19 genotypes and identified the isoenzymes of cytochrome P450 involved in this metabolic pathway. The kinetics of the -trifluoromethylphenol (TFMP) formation from fluoxetine was determined in human liver microsomes from three homozygous (wt/wt) and three heterozygous (wt/m1) extensive metabolizers (EMs) and three poor metabolizers (PMs) with m1 mutation (m1/m1) with respect to CYP2C19. The formation rate of TFMP was determined by gas chromatograph with electron-capture detection. The kinetics of TFMP formation was best described by the two-enzyme and single-enzyme Michaelis-Menten equation for liver microsomes from CYP2C19 EMs and PMs, respectively. The mean intrinsic clearance (Vmax/Km) for the high- and low-affinity component was 25.2 l/min/nmol and 3.8 l/min/nmol of cytochrome P450 in the homozygous EMs microsomes and 12.8 l/min/nmol and 2.9 l/min/nmol of cytochromecytochrome P450 in the heterozygous EMs microsomes, respectively. Omeprazole (a CYP2C19 substrate) at a high concentration and triacetyloleandomycin (a selective inhibitor of CYP3A4) substantially inhibited O-dealkylation of fluoxetine. Furthermore, fluoxetine O-dealkylation was correlated significantly with S-mephenytoin 4-hydroxylation at a low substrate concentration and midazolam 1 -hydroxylation at a high substrate concentration in liver microsomes of 11 Chinese individuals, respectively. Moreover, there were obvious differences in the O-dealkylation of fluoxetine in liver microsomes from different CYP2C19 genotypes and in microsomal fractions of different human-expressed lymphoblast P450s. The results demonstrated that polymorphic CYP2C19 and CYP3A4 enzymes were the major cytochrome P450 isoforms responsible for fluoxetine O-dealkylation, whereas CYP2C19 catalyzed the high-affinity O-dealkylation of fluoxetine, and its contribution to this metabolic reaction was gene dose-dependent.
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