周宏灏
药物反应个体差异和种族差异及其遗传机制
个性化签名
- 姓名:周宏灏
- 目前身份:
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学术头衔:
博士生导师
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学科领域:
药物化学
- 研究兴趣:药物反应个体差异和种族差异及其遗传机制
周宏灏,男,汉族,1939.5.29出生于湖南长沙。1962年毕业于武汉医学院医疗系。现为中南大学药理学国家重点学科首席教授,并任临床药理研究所所长、药品临床研究培训中心主任、临床药理国家培训中心主任,美国默沙东(Merck)国际临床药理奖学金评委(共6位评委)、国际药理学联合会(IUPHAR)遗传药理学和药物基因组学分会创始成员(Founding Member),国际药理学联合会药物代谢学会委员(Councillor)、中国药理学会常务理事、中国药物代谢专业委员会主任委员、湖南省药学会理事长、湖南省临床药理专业委员会主任委员。《Br J Clin Pharmacol》、《Current Pharmacogenomics》、《Asian J Durg Metab & Pharmacokin》、《Acta Pharmacol Sin》、《中华医学杂志》等10余家杂志编委。历任湖南医科大学药理教研室主任、遗传药理学研究所所长、基础与临床药理研究所所长、湖南医科大学副校长并兼任湖南省药品监督管理局副局长(顾问)。周宏灏教授自80年代初起始终围绕药物反应个体差异和种族差异及其遗传机制进行了系统、深入的研究,并取得了一系列令人瞩目的研究成果。1985年至1991年在美国Vanderbilt大学研究证实了药物反应种族差异,并深入阐明了产生机制,其研究成果在国际医药学术界引起强大反响,并获得美国临床研究学会颁发的Henry Christian奖,被国际同行誉为里程碑。1991年他从美国回国后,连续获得两项国家自然科学基金重点项目和三项美国中华医学基金会项目。创建了我国第一所遗传药理学研究所,在国内首次为研究生开设了遗传药理学课程,主编和出版了我国第一部《遗传药理学》研究生教材和《遗传药理学》专著,培养了90余名硕士和博士及博士后,造就了一支遗传药理学研究队伍。他是我国遗传药理学科的开拓者和带头人,在国际药学及药理学界享有较高声誉。先后20余次被国际学术会议邀请作大会专题报告或会议主席,并被斯坦福等美国、加拿大、日本、韩国和香港等国家和地区十多家大学邀请作学术报告。他的工作使我国遗传药理学和临床药理学研究处于世界先进水平。
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周宏灏
,-0001,():
-1年11月30日
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【期刊论文】Induction of polymorphic4`-hydroxylation of S-mephenytoin by rifampicin
周宏灏
,-0001,():
-1年11月30日
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周宏灏, Xing-Mei Han a, Dong-Sheng Ou-Yang a, Pei-Xin Lu b, Chang-Hong Jiang a, Yan Shu a, Xiao-Ping Chen a, Zhi-Rong Tan a and Hong-Hao Zhou a
Pharmacogenetics 2001, 11: 429-435,-0001,():
-1年11月30日
Either G-2964 or A734 in the human CYP1A2 gene was con
CYP1A2,, 17X/, 137X,, phenotype,, genotype,, polymorphism
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周宏灏, ZHOU-SHENG XIAO, JOYCE A. GOLDSTEIN, HONG-GUANG XIE, JOYCE BLAISDELL, WEI WANG, CHANG-HONG JIANG, FENG-XIANG YAN, NAN HE, SONG-LING HUANG, ZHEN-HUA XU and HONG-HAO ZHOU
Printed in U.S.A.281: 604-609, 1997,-0001,():
-1年11月30日
The incidence of the S-mephenytoin polymorphism was compared in two Chinese ethnic groups, Han (n=101) and Bai (n=202) by phenotype and genotype analysis. The frequency of poor metabolizers (PMs) in Han vs. Bai subjects was 19.8% vs. 13.4%. Han subjects had a higher frequency of the mutant CYP2C19m1 allele (0.366 vs. 0.257, P<.01) and a lower frequency of the wild-type allele (0.559 vs. 0.688, P<.01) than Bai subjects, which is consistent with the difference in the frequencies of PMs between the two ethnic groups. This results in a lower percentage of homozygous wild-type extensive metabolizers of mephenytoin (EMs) in Han subjects than in Bai subjects (40% vs. 59%, P=.005). Therefore, Han subjects may be more susceptible than Bai subjects to the drugs metabolized by the CYP2C19 enzyme. Ratios of urinary S/R-mephenytoin in homozygous EMs were lower than those of heterozygous EMs for both Han and Bai subjects, which shows a gene-dosage effect. Genotype analysis identified all but one PM as homozygous or heterozygous for the two known mutant CYP2C19m1 and/or CYP2C19m2 alleles. A single Bai PM outlier was shown to be heterozygous for CYP2C19m1 and a new mutant CYP2C19 allele containing a single amino acid change of Arg4333Trp433. A genotyping test demonstrated that only this one individual carried this rare allele (frequency of 0.0025 in Bai subjects).
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周宏灏, Lian-Sheng Wang, MD, Gan Zhou, Bing Zhu, PhD, Jun Wu, Jian-Gang Wang, A. M. Abd El-Aty, Tong Li, Jie Liu, Tian-Lun Yang, Dan Wang, BS, Xiang-Yang Zhong, and Hong-Hao Zhou, PhD Hunan and Guangzhou, China
CLINICAL PHARMACOLOGY & THERAPEUTICS 2004; 75 (3): 191-7,-0001,():
-1年11月30日
Objective: St John's wort, an extract of the medicinal plant Hypericum perforatum, is widely used as an herbal antidepressant. Although the ability of St John's wort to induce cytochrome P450 (CYP) 3A4-mediated reaction has been well established, the effect on CYP2C19 is still not determined. Thus the objective of this study was to determine the impact of St John's wort on the pharmacokinetic profiles of omeprazole and its metabolites. Methods: Twelve healthy adult men (6 CYP2C19*1/CYP2C19*1, 4 CYP2C19*2/CYP2C19*2 and 2 CYP2C19*2/CYP2C19*3) were nrolled in a 2-phase randomized crossover design. In each phase the volunteers received placebo or a 300-mg St John's wort tablet 3 times daily for 14 days. Then all subjects took a 20-mg omeprazole capsule orally. Blood samples were collected up to 12 hours after omeprazole administration. Omeprazole and its metabolites were quantified by use of HPLC with ultraviolet detection. Results: Omeprazole and its metabolites all exhibit CYP2C19 genotype-dependent pharmacokinetic profiles. After a 14-day treatment with St John's wort, substantial decreases in plasma concentrations of omeprazole were observed. The peak plasma concentration (Cmax) significantly decreased by 37.5%±13.3% (P=.001) in CYP2C19*2/CYP2C19*2 or *3 and by 49.6%±20.7% (P=.017) in CYP2C19*1/CYP2C19*1; the area under the concentration-time curve extrapolated to infinity [AUC(0-∞)] decreased by 37.9%±21.3% (P=.014) and 43.9%±23.7% (P=.011) in CYP2C19 mutant and wild genotypes, respectively. Moreover, the Cmax and AUC(0-∞) of omeprazole sulfone increased by 160.3%±45.5% (P=.001) and by 136.6%±84.6% (P=.014), 155.5%±58.8% (P=.001), and 158.7%±101.4% (P=.017) in mutant and wild genotypes, respectively. St John's wort increased the Cmax of 5-hydroxyomeprazole by 38.1% 30.5% (P=.028) and the AUC(0-∞) by 37.2%±26% (P=.005) in CYP2C19 wild-type subjects, whereas it did not produce any significant alterations to the corresponding pharmacokinetic parameters in subjects with variant genotypes. Conclusion: St John's wort induces both CYP3A4-catalyzed sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole and enormously decreases the plasma concentrations of omeprazole. Clinically relevant interactions with other drugs may occur and must be taken into account when St John's wort is being taken.
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【期刊论文】Isozyme-specific induction of low-dose aspirin on cytochrome P450 in healthy subjects
周宏灏, Xiao-Ping Chen, PhD, Zhi-Rong Tan, BS, Song-Lin Huang, Zheng Huang, MD, Dong-Sheng Ou-Yang, and Hong-Hao Zhou, MD Changsha, Hunan, hina
CLINICAL PHARMACOLOGY & THERAPEUTICS DECEMBER 2003; 73:264-271,-0001,():
-1年11月30日
Objective: This study was designed to define the effect of low-dose aspirin administration on the activity of cytochrome P450 (CYP) in normal human subjects. Methods: Aspirin, 50 mg daily, was given for 14 days to 18 nonsmoking healthy male volunteers. A modified 5-drug cocktail procedure consisting of caffeine, mephenytoin, metoprolol, chlorzoxazone, and midazolam was performed to simultaneously assess in vivo activity of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A, respectively. The activities were assessed on 4 occasions including at baseline, after 7 and 14 daily doses of aspirin, and at 7 days after discontinuation of aspirin. Concentrations of parent drugs and corresponding metabolites in biologic samples were assayed by reversed-phase HPLC. Results: Both 7-day and 14-day aspirin intake increased the activity of CYP2C19 significantly, as indicated by 4-hydroxymephenytoin urinary recovery (P<.001). Induction of low-dose aspirin on CYP2C19 was timedependent. CYP3A activity indices increased moderately but significantly by both 7-day and 14-day aspirin treatment (P<.05), but the percentage changes in CYP3A activity indices were not significant. Low-dose aspirin had no effect on CYP1A2, CYP2D6, and CYP2E1 in vivo activity by either 7-day or 14-day treatment. Conclusions: The effect of low-dose aspirin on CYPs was enzyme-specific. Both 7-day and 14-day low-dose aspirin induced the in vivo activities of CYP2C19 but did not affect the activities of CYP1A2, CYP2D6, and CYP2E1. The effect of low-dose aspirin on CYP3A activity awaits further confirmation. When low-dose aspirin is used in combination with drugs that are substrates of CYP2C19, doses of the latter should be adjusted to ensure their efficacy.
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【期刊论文】Assessment of cytochrome P450 activity by a five-drug cocktail approach
周宏灏, Bing Zhu, MD, PhD, Dong-Sheng Ou-Yang, MS, Xiao-Ping Chen, Song-Lin Huang, BS, Zhi-Rong Tan, Nan He, and Hong-Hao Zhou, MD Changsha, Hunan, China
CLINICAL PHARMACOLOGY & THERAPEUTICS DECEMBER 2001; 70: 455-461,-0001,():
-1年11月30日
Objectives: Our goal was to establish and validate a modified cocktail approach including probe drugs caffeine, chlorzoxazone, mephenytoin, metoprolol, and midazolam for simultaneous phenotyping of CYP1A2, CYP2E1, CYP2C19, CYP2D6, and CYP3A. Methods: The study was conducted in 14 healthy, nonsmoking male volunteers with a cocktail of 5 drugs consisting of 100mg caffeine, 200mg chlorzoxazone, 100mg mephenytoin, 100mg metoprolol, and 7.5mg midazolam in a randomized manner with a 7
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【期刊论文】Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19
周宏灏, Jiu-Hui Wang, MD, Zhao-Qian Liu, PhD, Wei Wang, MS, Xiao-Ping Chen, Yan Shu, Nan He, and Hong-Hao Zhou, MD Changsha, Hunan, China
CLINICAL PHARMACOLOGY & THERAPEUTICS DECEMBER 2001: 70: 42-47,-0001,():
-1年11月30日
Objective: Our objective was to evaluate the relationship between the disposition of sertraline and the presence of the CYP2C19 gene and to define the contribution of cytochrome P450 2C19 (CYP2C19) to sertraline N-demethylation. Methods: A single oral 100-mg dose of sertraline was administered to 6 subjects who were extensive metabolizers and 6 subjects who were poor metabolizers recruited from 77 healthy Chinese volunteers whose genotypes were predetermined by polymerase chain reaction-based amplification, followed by restriction fragment length polymorphism analysis. Phenotypes were determined by use of the omeprazole metabolic rate. The plasma concentrations of sertraline and desmethylsertraline were determined by gas chromatography with electron-capture detection. Results: Six poor metabolizers with m1 mutation had area under the plasma concentration versus time curve (AUC0-∞) values (983.6±199.3μg·h/L versus 697.6±133.0μg·h/L; P<0.05) and terminal elimination half-life values of sertraline (35.5±5.6 hours versus 23.5±4.4 hours; P<0.01) that were significantly higher than the values in 6 extensive metabolizers who were either homozygous or heterozygous for CYP2C19*1. The oral clearance of sertraline in poor metabolizers (105.3±19.4 L/h) was significantly lower than that of extensive metabolizers (148.4±28.6 L/h). The area under the concentration-time curve from 0 to 144 hours and the maximum plasma concentration of desmethylsertraline in poor metabolizers were significantly lower than the values of extensive metabolizers (627.6±203.8 μg·h/L versus 972.1±270.3μg·h/L; P<.05; and 23.6±6.5 nmol/L versus 32.4±8.2 nmol/L; P<.01;respectively). Conclusions: The polymorphic CYP2C19 appears to be a major enzyme involved in the N-demethylation of sertraline, and both extensive and poor metabolizers had marked differences in the disposition of sertraline.
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【期刊论文】Effect of the gene dosage of CYP2C19 on diazepam metabolism in Chinese subjects
周宏灏, Xu-Ping Qin, MD, a Hong-Guang Xie, PhD, b Wei Wang, MS, Nan He, Song-Lin Huang, BS, Zhen-Hua Xu, c Dong-Sheng Ou-Yang, Yong-Jin Wang, a and Hong-Hao Zhou
CLINICAL PHARMACOLOGY & THERAPEUTICS DECEMBER 1999: 66: 642-6,-0001,():
-1年11月30日
Objective: To determine whether the gene dosage of CYP2C19 affects the metabolism of diazepam and desmethyldiazepam in healthy Chinese subjects. Subjects and methods: Eighteen unrelated adult men were recruited for the study from a total of 101 healthy Chinese volunteers who had been screened for CYP2C19 phenotype and genotype. All subjects received a single oral dose (5mg) of diazepam, and the pharmacokinetics of diazepam and desmethyldiazepam were compared in six m1 homozygotes (m1/m1), six m1 heterozygotes (wt/m1), and six wild-type homozygotes (wt/wt). Results: The plasma elimination half-life values of diazepam (84.0
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