药物代谢与动力学研究中心（张洪建 教授）

张洪建 博士,教授
1994年获美国加州大学-戴维斯博士学位。1994-1998年期间在美国国家卫生研究院（NIH）从事博士后研究，主攻不饱和脂肪在中枢神经系统的代谢及褪黑激素对代谢酶的调控。1999年初加入美国Bristol-Myers Squibb制药公司，从事药物代谢动力学及成药性研究。2008年应邀加盟PharmaResources公司，主管临床前成药性研究。2011年7月受聘至18新利体育 ，现为18新利体育 医学部药学院特聘教授、博导,药学院药物代谢动力学研究中心主任。

张洪建教授长期从事药物代谢动力学及成药性研究。在多年的新药研发工作中, 积累了丰富的基础科研及新药创制经验，特别是在Bristol-Myers Squibb任职期间,曾带领或参与了多个研究小组，先后发现了十几个可用于治疗多种疾病的候选药，如糖尿病、肥胖症、心血管疾病、癌症和免疫系统疾病等；多次参加美国药监局 (FDA) 新药申请 (IND) 的药物代谢动力学评估及毒理研究工作，并撰写各种申报资料。张洪建教授不仅擅长药物处置机制(代谢酶、转运体)的基础研究,同时善于运用成药性原理及最先进的技术手段指导先导化合物的优化、候选药物的临床前研究及临床一期实验设计；在多个国际著名学术杂志发表科学论文46篇。

主要研究方向
1. 药物代谢反应类型鉴定、代谢酶(CYP、UGT、SULT等)基因亚型对清除率的影响
2. 药物外排及摄取转运体对ADME过程及PK-PD相关性的作用
3. 基于代谢酶及转运体介导的药物相互作用及药物安全性评估

代表性论文
1. Development of a canine model to enable the preclinical assessment of pH-dependent absorption of test compounds. Fancher RM, Zhang H, Sleczka B, Derbin G, Rockar R, Marathe P. J Pharm Sci. 2011 Jul; 100(7):2979-88.
2. Repaglinide-gemfibrozil drug interaction: inhibition of repaglinide glucuronidation as a potential additional contributing mechanism. Gan J, Chen W, Shen H, Gao L, Hong Y, Tian Y, Li W, Zhang Y, Tang Y, Zhang H, Humphreys WG, Rodrigues AD. Br J Clin Pharmacol. 2010 Dec; 70(6):870-80.
3. Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f] [1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases. Liu C, Lin J, Wrobleski ST, Lin S, Hynes J, Wu H, Dyckman AJ, Li T, Wityak J, Gillooly KM, Pitt S, Shen DR, Zhang RF, McIntyre KW, Salter-Cid L, Shuster DJ, Zhang H, Marathe PH, Doweyko AM, Sack JS, Kiefer SE, Kish KF, Newitt JA, McKinnon M, Dodd JH, Barrish JC, Schieven GL, Leftheris K. J Med Chem. 2010 Sep 23; 53(18):6629-39.
4. Preclinical pharmacokinetics and in vitro metabolism of BMS-690514, a potent inhibitor of EGFR and VEGFR2. Marathe P, Tang Y, Sleczka B, Rodrigues D, Gavai A, Wong T, Christopher L, Zhang H. J Pharm Sci. 2010 Aug; 99(8):3579-93.
5. Confirmation that cytochrome P450 2C8 (CYP2C8) plays a minor role in (S)-(+)- and (R)-(-)-ibuprofen hydroxylation in vitro. Chang SY, Li W, Traeger SC, Wang B, Cui D, Zhang H, Wen B, Rodrigues AD. Drug Metab Dispos. 2008 Dec; 36(12):2513-22.
6. In vitro evaluation of reversible and irreversible cytochrome P450 inhibition: current status on methodologies and their utility for predicting drug-drug interactions. Fowler S, Zhang H. AAPS J. 2008 Jun; 10(2):410-24.
7. Cytochrome P450 reaction-phenotyping: an industrial perspective. Zhang H, Davis CD, Sinz MW, Rodrigues AD. Expert Opin Drug Metab Toxicol. 2007 Oct; 3(5):667-87.
8. Characterization of the UDP glucuronosyltransferase activity of human liver microsomes genotyped for the UGT1A1*28 polymorphism. Zhang D, Zhang D, Cui D, Gambardella J, Ma L, Barros A, Wang L, Fu Y, Rahematpura S, Nielsen J, Donegan M, Zhang H, Humphreys WG. Drug Metab Dispos. 2007 Dec; 35(12):2270-80.
9. Effect of commonly used organic solvents on the kinetics of cytochrome P450 2B6- and 2C8-dependent activity in human liver microsomes. Vuppugalla R, Chang SY, Zhang H, Marathe PH, Rodrigues DA. Drug Metab Dispos. 2007 Nov; 35(11):1990-5.
10. Reduction of site-specific CYP3A-mediated metabolism for dual angiotensin and endothelin receptor antagonists in various in vitro systems and in cynomolgus monkeys. Zhang H, Zhang D, Li W, Yao M, D'Arienzo C, Li YX, Ewing WR, Gu Z, Zhu Y, Murugesan N, Shyu WC, Humphreys WG. Drug Metab Dispos. 2007 May; 35(5):795-805.
11. Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol: a new look at an old drug.
Zhang H, Cui D, Wang B, Han YH, Balimane P, Yang Z, Sinz M, Rodrigues AD. Clin Pharmacokinet. 2007; 46(2):133-57.
12. Involvement of multiple cytochrome P450 and UDP-glucuronosyltransferase enzymes in the in vitro metabolism of muraglitazar. Zhang D, Wang L, Chandrasena G, Ma L, Zhu M, Zhang H, Davis CD, Humphreys WG. Drug Metab Dispos. 2007 Jan; 35(1):139-49.

张洪建课题组成员

汪维鹏 博士，副教授
2002年毕业于中国药科大学中药药理学专业，于2007年获得中国药科大学药物分析学专业博士。2008-2011年期间在18新利体育 医学生物技术研究所从事博士后研究。2010年受聘于18新利体育 医学部药学院药物分析教研室副教授、硕导。

主要研究方向
1. 基于药物转运体/代谢酶的消化道肿瘤个体化用药
2. 药物转运体/代谢酶在消化道肿瘤发生发展及化疗反应中的作用机制

代表性论文
1. Wang WP, Sun J, Li F, et al. A frequent somatic mutation in B7-H1 3’-UTR leads to protein over-expression in gastric cancer by disrupting miR-570 binding. Hum Mutat, in press.
2. Cao P, Wang QJ, Zhu XT, Zhou H, Li R, Wang WP*. Quantitative determination of allele frequency in pooled DNA by using sequencing method. J Chromatogr B 2011 Mar 1;879(7-8):527-32.
3. Wang WP*, Zhang XD, Zhou GH. High-throughput genotyping by coupling adapter-ligation mediated allele-specific amplification with microplate array parallel gel electrophoresis. Mol Biotechnol 2010 Jan;44(1):1-7.
4. Wang WP*, Zhang RH, Wu P, Wang S, Li R. Estimation of allele frequency in pooled DNA by using PCR-RFLP combined with microchip electrophoresis. J Chromatogr B 2009 May 15;877(14-15):1603-6.
5. Ren L, Gao YZ, Yin JH, Shi WX, Yu XW, Xie HP*, Wang WP*. The determination for the three genotypes of D16S539 locus based on near-infrared spectroscopy and chemical pattern recognition. Anal Chim Acta 2009 Apr 13;638(2):202-8.
6. Wang WP, Sun WM, Wu WJ, Zhou GH. Improved adapter-ligation mediated allele-specific amplification for multiplex genotyping by using software. Electrophoresis 2008 Apr;29(7):1490-501.
7. Wang WP, Wu WJ, Ni KY, Zhou GH. Detection of avian influenza a virus by using Pyrosequencing. Chinese J Anal Chem 2008 Jun, 36(6): 775-780.
8. Wang WP, Ni KY, Zhou GH. Association of IL1B polymorphisms with gastric cancer in a Chinese population. Clin Biochem 2007, 40: 218-225.
9. Wang WP, Ni KY, Zhou GH. Multiplex SNP genotyping by adapter-ligation mediated allele-specific amplification. Anal Biochem 2006, 355(2): 240-248.
10. Wang WP, Ni KY, Zhou GH. Microchip electrophoresis coupled with multiplex polymerase chain reaction for typing multiple single nucleotide polymorphisms simultaneously. Chin J Anal Chem 2006, 34(10): 1389-1394.

承担或参与的科研项目
1. 负性协同刺激分子B7-H1在胃癌组织中表达的调节机制研究（国家青年自科学基金项目，No. 30901360，2010年1月～2012年12月）；
2. 肠癌中协同刺激分子B7-H1表达的调节机制研究（中国博士后科学基金资项目，No. 20080441077，2008年9月～2010年8月，已完成）；
3. 肠癌组织中协同刺激分子B7-H1表达的机制研究（江苏省博士后科研计划助项目，No. 0802026C，2008年9月～2010年8月，已完成）；
4. 协同刺激分子B7-H1在肠癌免疫逃逸中的调节机制研究（18新利体育 青年教自然科学基金项目，No.Q3132819，2008年11月～2010年10月，已完成）。

贵春山 博士，副教授
2000年毕业于四川大学，获化学学士学位；2005年毕业于中科院上海药物研究所，获有机化学博士学位。2005-2010年任美国堪萨斯大学医学中心博士后研究员，从事药物转运蛋白结构和功能的研究。2011年受聘于18新利体育 医学部药学院副教授。

主要研究方向
1. 药物转运蛋白及其在新药研发中的作用
2. 药物处置机制及药物动力学

代表性论文
1. Gui C, Obaidat A, Chaguturu R, Hagenbuch B. Development of a cell-based high-throughput assay to screen for inhibitors of organic anion transporting polypeptides 1B1 and 1B3. Curr. Chem. Genomics 2010, 4: 1-8.
2. Gui C, Hagenbuch B. Cloning/characterization of the canine organic anion transporting polypeptide 1b4 (Oatp1b4) and classification of the canine OATP/SLCO members. Comp. Biochem. Physiol. 2010, 151: 393-399.
3. Gui C, Hagenbuch B. Role of transmembrane domain 10 for the function of organic anion transporting polypeptide 1B1. Protein Sci. 2009, 18: 2298-2306.
4. Gui C, Wahlgren B, Lushington GH, Hagenbuch B. Identification, Ki determination and CoMFA analysis of nuclear receptor ligands as competitive inhibitors of OATP1B1-mediated estradiol-17β-glucuronide transport. Pharmacol. Res. 2009, 60: 50-56.
5. Gui C, Hagenbuch B. Amino acid residues in transmembrane domain 10 of organic anion transporting polypeptide 1B3 are critical for cholecystokinin octapeptide transport. Biochemistry 2008, 47: 9090-9097.
6. Gui C, Miao Y, Thompson L, Wahlgren B, Mock M, Stieger B, Hagenbuch B. Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3. Eur. J. Pharmacol. 2008, 584: 57-65.
7. B. Hagenbuch, C. Gui. Xenobiotic transporters of the human organic anion transporting polypeptides (OATP) family. Xenobiotica 2008, 38: 778-801.
8. Gui C, Zhu W, Chen G, Luo X, Liew OW, Puah CM, Shen J, et al. Understanding the regulation mechanisms of PAF receptor by agonists and antagonists: molecular modeling and molecular dynamics simulation studies. Proteins 2007, 67: 41-52.
9. Chen L, Gui C, Luo X, Yang Q, Günther S, Scandella E, Drosten C, et al. Cinanserin is an inhibitor of the 3C-like proteinase of severe acute respiratory syndrome coronavirus and strongly reduces virus replication in vitro. J. Virol. 2005, 79: 7095-7103.