药物代谢酶表型鉴定的研究现状
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摘要
在新药临床前研究中,应对药物的代谢酶表型进行鉴定,获得其主要代谢酶的消除比例,为药物-药物相互作用研究提供重要信息。本文对人体内主要药物代谢酶,包括细胞色素P450酶、尿苷二磷酸葡萄糖醛酸转移酶、含黄素单加氧酶和醛氧化酶的酶表型鉴定研究现状进行综述。
Phenotyping of drug-metabolizing enzymes was necessary in the preclinical study of a new drug,Which provides important information for the drug-drug interaction. We reviewed the research status on the phenotyping of major drug-metabolizing enzymes, including cytochrome P450 s, uridine 5'-diphosphate glucuronosyltransferases, flavin-containing monooxygenases and aldehyde oxidases.
Phenotyping of drug-metabolizing enzymes was necessary in the preclinical study of a new drug,Which provides important information for the drug-drug interaction. We reviewed the research status on the phenotyping of major drug-metabolizing enzymes, including cytochrome P450 s, uridine 5'-diphosphate glucuronosyltransferases, flavin-containing monooxygenases and aldehyde oxidases.
引文
[1]Nassar FA,Rodrigues DA.An introduction to metabolic reaction phenotyping[M].New York:John Wiley&Sons,2009:391-447.
[2]Venkatakrishnan K,Von Moltke LL,Greenblatt DJ.Human drug metabolism and the cytochromes P450:application and relevance of in vitro models[J].J Clin Pharmacol,2001,41(11):1149-1179.
[3]Huang SM,Temple R,Throckmorton DC,et al.FDAGuidance Page.Draft Guidance for Industry:Drug interaction studies-study design,data analysis,and implications for dosing and labeling[J].Clin Pharmacol Ther,2007,81(2):298-304.
[4]Rodrigues AD.Integrated cytochrome P450 reaction phenotyping:attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes[J].Biochem Pharmacol,1999,57(5):465-480.
[5]Zientek MA,Youdim K.Reaction phenotyping:advances in the experimental strategies used to characterize the contribution of drug-metabolizing enzymes[J].Drug Metab Dispos,2015,43(1):163-181.
[6]Walsky RL,Obach RS,Hyland R,et al.Selective mechanism-based inactivation of CYP3A4 by CYP3cide(PF-04981517)and its utility as an in vitro tool for delineating the relative roles of CYP3A4 versus CYP3A5 in the metabolism of drugs[J].Drug Metab Dispos,2012,40(9):1686-1697.
[7]Walsky RL,Boldt SE.In vitro cytochrome P450 inhibition and induction[J].Curr Drug Metab,2008,9(9):928-939.
[8]Emoto C,Murayama N,Rostami-Hodjegan A,et al.Methodologies for investigating drug metabolism at the early drug discovery stage:prediction of hepatic drug clearance and P450 contribution[J].Curr Drug Metab,2010,11(8):678-685.
[9]Venkatakrishnan K,von Moltke LL,Greenblatt DJ.Application of the relative activity factor approach in scaling from heterologously expressed cytochromes p450 to human liver microsomes:studies on amitriptyline as a model substrate[J].J Pharmacol Exp Ther,2001,297(1):326-337.
[10]杨少林,熊友健,方平飞,等.呋喃香豆素类化合物对CYP450酶系影响的研究进展[J].中南药学,2011,9(1):45-49.
[11]Proctor NJ,Tucker GT,Rostami-Hodjegan A.Predicting drug clearance from recombinantly expressed CYPs:intersystem extrapolation factors[J].Xenobiotica,2004,34(2):151-178.
[12]Chen Y,Liu L,Nguyen K,et al.Utility of intersystem extrapolation factors in early reaction phenotyping and the quantitative extrapolation of human liver microsomal intrinsic clearance using recombinant cytochromes P450[J].Drug Metab Dispos,2011,39(3):373-382.
[13]Stringer RA,Strain-Damerell C,Nicklin P,et al.Evaluation of recombinant cytochrome P450 enzymes as an in vitro system for metabolic clearance predictions[J].Drug Metab Dispos,2009,37(5):1025-1034.
[14]Klein TE,Altman RB,Eriksson N,et al.International warfarin Pharmacogenetics Consortium.Estimation of the warfarin dose with clinical and pharmacogenetic data[J].NEngl J Med,2009,360(8):753-764.
[15]Aithal GP,Day CP,Kesteven PJ,et al.Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications[J].Lancet,1999,353(7):717-719.
[16]www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics.
[17]李晋岗,张颖,罗芳梅,等.HPLC-MS/MS法研究人尿中甲磺酸桂哌齐特的主要代谢产物[J].中南药学,2014,12(8):782-785.
[18]Lu AY,Wang RW,Lin JH.Cytochrome P450 in vitro reaction phenotyping:a re-evaluation of approaches used for P450 isoform identification[J].Drug Metab Dispos,2003,31(4):345-350.
[19]Meech R,Mackenzie PI.Structure and function of uridine diphosphate glucuronosyltransferases[J].Clin Exp Pharmacol Physiol,1997,24(12):907-915.
[20]Williams JA,Hyland R,Jones BC,et al.Drug-drug interactions for UDP-glucuronosyltransferase substrates:a pharmacokinetic explanation for typically observed low exposure(AUCi/AUC)ratios[J].Drug Metab Dispos,2004,32(11):1201-1208.
[21]Court M.In vitro identification of UDP-glucuronosyltransferases(UGTs)involved in drug metabolism.In:Yan Z,Caldwell G,eds[M].Optimization in Drug Discovery:Humana Press;2004:185-202.
[22]Basu NK,Kovarova M,Garza A,et al.Phosphorylation of a UDP-glucuronosyltransferase regulates substrate specificity[J].Proc Natl Acad Sci USA,2005,102(18):6285-6290.
[23]Walsky RL,Bauman JN,Bourcier K,et al.Optimized assays for human UDP-glucuronosyltransferase(UGT)activities:altered alamethicin concentration and utility to screen for UGT inhibitors[J].Drug Metab Dispos,2012,40(5):1051-1065.
[24]Fallon JK,Harbourt DE,Maleki SH,et al.Absolute quantification of human uridine-diphosphate glucuronosyl transferase(UGT)enzyme isoforms 1A1 and 1A6by tandem LC-MS[J].Drug Metab Lett,2008,2(3):210-222.
[25]Fallon JK,Neubert H,Goosen TC,et al.Targeted precise quantification of 12 human recombinant uridine-diphosphate glucuronosyl transferase 1A and 2B isoforms using nano-ultra-high-performance liquid chromatography/tandem mass spectrometry with selected reaction monitoring[J].Drug Metab Dispos,2013,41(12):2076-2080.
[25]Katsura T,Matsumoto S,Yanagihara K,et al.UG-T1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients[J].Int J Clin Oncol,2009,14(1):136-142.
[26]Rosalia DA,Teresa E.FMO3 allelic variants in Sicilianand Sardinian populations:trimethylaminuria and absence of fish-like body odor[J].Gene,2013,515(2):410-415.
[27]蔡晋艳.甲巯咪唑对伊托必利药动学的影响及其与FMO3基因多态性的关系[D].长沙:中南大学,2009.
[28]Hutzler JM,Yang YS,Albaugh D,et al.Characterization of aldehyde oxidase enzyme activity in cryopreserved human hepatocytes[J].Drug Metab Dispos,2012,40(2):267-275.
[29]Chauret N,Gauthier A,Nicoll-Griffith DA.Effect of common organic solvents on in vitro cytochrome P450-mediated metabolic activities in human liver microsomes[J].Drug Metab Dispos,1998,26(1):1-4.
[30]Obach RS.Potent inhibition of human liver aldehyde oxidase by raloxifene[J].Drug Metab Dispos,2004,32(1):89-97.
[31]Choughule KV,Barr JT,Jones JP.Evaluation of rhesus monkey and guinea pig hepatic cytosol fractions as models for human aldehyde oxidase[J].Drug Metab Dispos,2013,41(10):1852-1858.
[32]Pearson JT,Wahlstrom JL,Dickmann LJ,et al.Differential time-dependent inactivation of P450 3A4 and P450 3A5 by raloxifene:a key role for C239 in quenching reactive intermediates[J].Chem Res Toxicol,2007,20(12):1778-1786.
[33]Price RJ,Mistry H,Wield PT,et al.Comparison of the toxicity of allyl alcohol,coumarin and menadione in precision-cut rat,guinea-pig,cynomolgus monkey and human liver slices[J].Arch Toxicol,1996,71(1-2):107-111.
[34]Strelevitz TJ,Orozco CC,Obach RS.Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes:estimation of the contribution of aldehyde oxidase to metabolic clearance[J].Drug Metab Dispos,2012,40(7):1441-1448.
[35]Barr JT,Jones JP,Joswig-Jones CA,et al.Absolute quantification of aldehyde oxidase protein in human liver using liquid chromatography-tandem mass spectrometry[J].Mol Pharm,2013,10(10):3842-3849.
[36]Zientek MA,Youdim K.Reaction phenotyping:advances in the experimental strategies used to characterize the contribution of drug-metabolizing enzymes[J].Drug Metab Dispos,2015,43(1):163-181.
[37]Riches Z,Stanley EL,Bloomer JC,et al.Quantitative evaluation of the expression and activity of five major sulfotransferases(SULTs)in human tissues:the SULT“pie”[J].Drug Metabol Dispos,2009,37(11):2255-2261.
[38]姜金方,李秀立,陈笑艳,等.肝脏和肠道酯酶在药物代谢及新药研发中的作用[J].药学学报,2018,53(2):177-185.
[39]Argikar UA,Potter PM,Hutzler JM,et al.Challenges and opportunities with non-CYP enzymes aldehyde oxidase,carboxylesterase,and UDP-glucuronosyltransferase:focus on reaction phenotyping and prediction of human clearance[J].AAPS J,2016,18(6):1391-1405.
[40]Shimizu M,Fukami T,Nakajima M,et al.Screening of specific inhibitors for human carboxylesterases or arylacetamide deacetylase[J].Drug Metab Dispos,2014,42(7):1103-1109.
[41]Keith FT,Sinead B,Jeff OS,et al.Monoamine oxidases:certainties and uncertainties[J].Curr Med Chem,2004,11(15):1965-1982.
[42]周雷,钟大放,陈笑艳.非P450酶介导的药物氧化代谢研究进展[J].药学学报,2017,52(1):8-18.
[43]曹亚杰,曹伟,余奇,等.吴茱萸次碱在人肝微粒体中对细胞色素P450酶的抑制作用[J].中南药学,2005,3(4):243-245.
[44]周艳钢,李焕德.体内药物代谢研究的意义与应用[J].中南药学,2009,7(1):46-50.
[2]Venkatakrishnan K,Von Moltke LL,Greenblatt DJ.Human drug metabolism and the cytochromes P450:application and relevance of in vitro models[J].J Clin Pharmacol,2001,41(11):1149-1179.
[3]Huang SM,Temple R,Throckmorton DC,et al.FDAGuidance Page.Draft Guidance for Industry:Drug interaction studies-study design,data analysis,and implications for dosing and labeling[J].Clin Pharmacol Ther,2007,81(2):298-304.
[4]Rodrigues AD.Integrated cytochrome P450 reaction phenotyping:attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes[J].Biochem Pharmacol,1999,57(5):465-480.
[5]Zientek MA,Youdim K.Reaction phenotyping:advances in the experimental strategies used to characterize the contribution of drug-metabolizing enzymes[J].Drug Metab Dispos,2015,43(1):163-181.
[6]Walsky RL,Obach RS,Hyland R,et al.Selective mechanism-based inactivation of CYP3A4 by CYP3cide(PF-04981517)and its utility as an in vitro tool for delineating the relative roles of CYP3A4 versus CYP3A5 in the metabolism of drugs[J].Drug Metab Dispos,2012,40(9):1686-1697.
[7]Walsky RL,Boldt SE.In vitro cytochrome P450 inhibition and induction[J].Curr Drug Metab,2008,9(9):928-939.
[8]Emoto C,Murayama N,Rostami-Hodjegan A,et al.Methodologies for investigating drug metabolism at the early drug discovery stage:prediction of hepatic drug clearance and P450 contribution[J].Curr Drug Metab,2010,11(8):678-685.
[9]Venkatakrishnan K,von Moltke LL,Greenblatt DJ.Application of the relative activity factor approach in scaling from heterologously expressed cytochromes p450 to human liver microsomes:studies on amitriptyline as a model substrate[J].J Pharmacol Exp Ther,2001,297(1):326-337.
[10]杨少林,熊友健,方平飞,等.呋喃香豆素类化合物对CYP450酶系影响的研究进展[J].中南药学,2011,9(1):45-49.
[11]Proctor NJ,Tucker GT,Rostami-Hodjegan A.Predicting drug clearance from recombinantly expressed CYPs:intersystem extrapolation factors[J].Xenobiotica,2004,34(2):151-178.
[12]Chen Y,Liu L,Nguyen K,et al.Utility of intersystem extrapolation factors in early reaction phenotyping and the quantitative extrapolation of human liver microsomal intrinsic clearance using recombinant cytochromes P450[J].Drug Metab Dispos,2011,39(3):373-382.
[13]Stringer RA,Strain-Damerell C,Nicklin P,et al.Evaluation of recombinant cytochrome P450 enzymes as an in vitro system for metabolic clearance predictions[J].Drug Metab Dispos,2009,37(5):1025-1034.
[14]Klein TE,Altman RB,Eriksson N,et al.International warfarin Pharmacogenetics Consortium.Estimation of the warfarin dose with clinical and pharmacogenetic data[J].NEngl J Med,2009,360(8):753-764.
[15]Aithal GP,Day CP,Kesteven PJ,et al.Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications[J].Lancet,1999,353(7):717-719.
[16]www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics.
[17]李晋岗,张颖,罗芳梅,等.HPLC-MS/MS法研究人尿中甲磺酸桂哌齐特的主要代谢产物[J].中南药学,2014,12(8):782-785.
[18]Lu AY,Wang RW,Lin JH.Cytochrome P450 in vitro reaction phenotyping:a re-evaluation of approaches used for P450 isoform identification[J].Drug Metab Dispos,2003,31(4):345-350.
[19]Meech R,Mackenzie PI.Structure and function of uridine diphosphate glucuronosyltransferases[J].Clin Exp Pharmacol Physiol,1997,24(12):907-915.
[20]Williams JA,Hyland R,Jones BC,et al.Drug-drug interactions for UDP-glucuronosyltransferase substrates:a pharmacokinetic explanation for typically observed low exposure(AUCi/AUC)ratios[J].Drug Metab Dispos,2004,32(11):1201-1208.
[21]Court M.In vitro identification of UDP-glucuronosyltransferases(UGTs)involved in drug metabolism.In:Yan Z,Caldwell G,eds[M].Optimization in Drug Discovery:Humana Press;2004:185-202.
[22]Basu NK,Kovarova M,Garza A,et al.Phosphorylation of a UDP-glucuronosyltransferase regulates substrate specificity[J].Proc Natl Acad Sci USA,2005,102(18):6285-6290.
[23]Walsky RL,Bauman JN,Bourcier K,et al.Optimized assays for human UDP-glucuronosyltransferase(UGT)activities:altered alamethicin concentration and utility to screen for UGT inhibitors[J].Drug Metab Dispos,2012,40(5):1051-1065.
[24]Fallon JK,Harbourt DE,Maleki SH,et al.Absolute quantification of human uridine-diphosphate glucuronosyl transferase(UGT)enzyme isoforms 1A1 and 1A6by tandem LC-MS[J].Drug Metab Lett,2008,2(3):210-222.
[25]Fallon JK,Neubert H,Goosen TC,et al.Targeted precise quantification of 12 human recombinant uridine-diphosphate glucuronosyl transferase 1A and 2B isoforms using nano-ultra-high-performance liquid chromatography/tandem mass spectrometry with selected reaction monitoring[J].Drug Metab Dispos,2013,41(12):2076-2080.
[25]Katsura T,Matsumoto S,Yanagihara K,et al.UG-T1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients[J].Int J Clin Oncol,2009,14(1):136-142.
[26]Rosalia DA,Teresa E.FMO3 allelic variants in Sicilianand Sardinian populations:trimethylaminuria and absence of fish-like body odor[J].Gene,2013,515(2):410-415.
[27]蔡晋艳.甲巯咪唑对伊托必利药动学的影响及其与FMO3基因多态性的关系[D].长沙:中南大学,2009.
[28]Hutzler JM,Yang YS,Albaugh D,et al.Characterization of aldehyde oxidase enzyme activity in cryopreserved human hepatocytes[J].Drug Metab Dispos,2012,40(2):267-275.
[29]Chauret N,Gauthier A,Nicoll-Griffith DA.Effect of common organic solvents on in vitro cytochrome P450-mediated metabolic activities in human liver microsomes[J].Drug Metab Dispos,1998,26(1):1-4.
[30]Obach RS.Potent inhibition of human liver aldehyde oxidase by raloxifene[J].Drug Metab Dispos,2004,32(1):89-97.
[31]Choughule KV,Barr JT,Jones JP.Evaluation of rhesus monkey and guinea pig hepatic cytosol fractions as models for human aldehyde oxidase[J].Drug Metab Dispos,2013,41(10):1852-1858.
[32]Pearson JT,Wahlstrom JL,Dickmann LJ,et al.Differential time-dependent inactivation of P450 3A4 and P450 3A5 by raloxifene:a key role for C239 in quenching reactive intermediates[J].Chem Res Toxicol,2007,20(12):1778-1786.
[33]Price RJ,Mistry H,Wield PT,et al.Comparison of the toxicity of allyl alcohol,coumarin and menadione in precision-cut rat,guinea-pig,cynomolgus monkey and human liver slices[J].Arch Toxicol,1996,71(1-2):107-111.
[34]Strelevitz TJ,Orozco CC,Obach RS.Hydralazine as a selective probe inactivator of aldehyde oxidase in human hepatocytes:estimation of the contribution of aldehyde oxidase to metabolic clearance[J].Drug Metab Dispos,2012,40(7):1441-1448.
[35]Barr JT,Jones JP,Joswig-Jones CA,et al.Absolute quantification of aldehyde oxidase protein in human liver using liquid chromatography-tandem mass spectrometry[J].Mol Pharm,2013,10(10):3842-3849.
[36]Zientek MA,Youdim K.Reaction phenotyping:advances in the experimental strategies used to characterize the contribution of drug-metabolizing enzymes[J].Drug Metab Dispos,2015,43(1):163-181.
[37]Riches Z,Stanley EL,Bloomer JC,et al.Quantitative evaluation of the expression and activity of five major sulfotransferases(SULTs)in human tissues:the SULT“pie”[J].Drug Metabol Dispos,2009,37(11):2255-2261.
[38]姜金方,李秀立,陈笑艳,等.肝脏和肠道酯酶在药物代谢及新药研发中的作用[J].药学学报,2018,53(2):177-185.
[39]Argikar UA,Potter PM,Hutzler JM,et al.Challenges and opportunities with non-CYP enzymes aldehyde oxidase,carboxylesterase,and UDP-glucuronosyltransferase:focus on reaction phenotyping and prediction of human clearance[J].AAPS J,2016,18(6):1391-1405.
[40]Shimizu M,Fukami T,Nakajima M,et al.Screening of specific inhibitors for human carboxylesterases or arylacetamide deacetylase[J].Drug Metab Dispos,2014,42(7):1103-1109.
[41]Keith FT,Sinead B,Jeff OS,et al.Monoamine oxidases:certainties and uncertainties[J].Curr Med Chem,2004,11(15):1965-1982.
[42]周雷,钟大放,陈笑艳.非P450酶介导的药物氧化代谢研究进展[J].药学学报,2017,52(1):8-18.
[43]曹亚杰,曹伟,余奇,等.吴茱萸次碱在人肝微粒体中对细胞色素P450酶的抑制作用[J].中南药学,2005,3(4):243-245.
[44]周艳钢,李焕德.体内药物代谢研究的意义与应用[J].中南药学,2009,7(1):46-50.