Sitokrom P450 Polimorfizmleri ve İlaç Metabolizması
Özet
Sitokrom P450 (CYP450) enzimleri, hem endojen bileşiklerin hem de ksenobiyotiklerin metabolizmasında kritik öneme sahip bir hemoprotein süperfamilyasıdır. Bu enzimler, klinik kullanımdaki ilaçların farmakokinetik özelliklerini doğrudan etkiler. Özellikle CYP1, CYP2 ve CYP3 enzim aileleri ilaç metabolizmasında ön plana çıkmaktadır. Genetik polimorfizmler (tek nükleotid polimorfizmleri, insersiyon-delesyonlar ve kopya sayısı varyasyonları), bireyler arasında enzim aktivitelerinde yavaş metabolizörden çok hızlı metabolizöre uzanan geniş bir fenotipik varyasyona yol açar. Bu durum, kodein, varfarin, fenitoin, klopidogrel ve takrolimus gibi dar terapötik indekse sahip ilaçların etkinliğini veya toksisite riskini belirgin şekilde değiştirir. Günümüzde, teknolojik gelişmelerle birlikte geleneksel genotiplemeden genom dizileme çağına geçilmiş ve binlerce nadir varyant tanımlanmıştır. Bu durum tedavinin bireyselleştirilmesine katkı sağlasa da, varyantların klinik öneminin netleştirilmesi konusunda büyük ölçekli fonksiyonel analizlere duyulan ihtiyacı artırmıştır. Farmakogenetik kılavuzların klinik rutine entegrasyonu; organizasyonel, etik ve finansal engeller nedeniyle yavaş ilerlese de, gelecekte elektronik tıbbi kayıtların geliştirilmesi ve kişiselleştirilmiş tıp uygulamaları ile tedavi başarısının optimize edilmesi hedeflenmektedir.
Cytochrome P450 (CYP450) enzymes represent a hemoprotein superfamily that plays a critical role in metabolizing both endogenous compounds and xenobiotics. These enzymes directly impact the pharmacokinetic profiles of clinically utilized drugs, with CYP1, CYP2, and CYP3 families being paramount in drug biotransformation. Genetic polymorphisms, including single nucleotide polymorphisms, insertion-deletions, and copy number variations, lead to significant interindividual phenotypic variations ranging from poor to ultrarapid metabolizers. This variability substantially alters the efficacy or toxicity profiles of narrow therapeutic index drugs such as codeine, warfarin, phenytoin, clopidogrel, and tacrolimus. While technological advancements have shifted the paradigm from traditional genotyping to large-scale genome sequencing, identifying thousands of rare variants, it has also introduced challenges in clinical interpretation, necessitating advanced computational and functional analyses. Despite the slow integration of pharmacogenetic testing into routine clinical practice due to organizational, ethical, and financial hurdles, the continuous refinement of evidence-based guidelines and electronic medical records holds promise for the future. Ultimately, factoring in these genetic differences along with environmental influences remains vital to optimizing personalized therapeutic outcomes.
Referanslar
Nelson DR, Zeldin DC, Hoffman SMG, Maltais LJ, Wain HM, Nebert DW. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants. Pharmacogenetics. 2004;14(1):1-18. doi:10.1097/00008571-200401000-00001
Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet (London, England). 2002;360(9340):1155-1162. doi:10.1016/S0140-6736(02)11203-7
Zanger UM, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem. 2008;392(6):1093-1108. doi:10.1007/s00216-008-2291-6
Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138(1):103-141. doi:10.1016/j.pharmthera.2012.12.007
Gaedigk A, Ingelman-Sundberg M, Miller NA, et al. The Pharmacogene Variation (PharmVar) Consortium: Incorporation of the Human Cytochrome P450 (CYP) Allele Nomenclature Database. Clin Pharmacol Ther. 2018;103(3):399-401. doi:10.1002/cpt.910
Zhang H-F, Wang H-H, Gao N, et al. Physiological Content and Intrinsic Activities of 10 Cytochrome P450 Isoforms in Human Normal Liver Microsomes. J Pharmacol Exp Ther. 2016;358(1):83-93. doi:10.1124/jpet.116.233635
Zhou S-F, Wang B, Yang L-P, Liu J-P. Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev. 2010;42(2):268-354. doi:10.3109/03602530903286476
Gunes A, Dahl M-L. Variation in CYP1A2 activity and its clinical implications: influence of environmental factors and genetic polymorphisms. Pharmacogenomics. 2008;9(5):625-637. doi:10.2217/14622416.9.5.625
Zhou Y, Ingelman-Sundberg M, Lauschke VM. Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects. Clin Pharmacol Ther. 2017;102(4):688-700. doi:10.1002/cpt.690
Fuhr U, Rost KL, Engelhardt R, et al. Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations. Pharmacogenetics. 1996;6(2):159-176. doi:10.1097/00008571-199604000-00003
Amin N, Byrne E, Johnson J, et al. Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM. Mol Psychiatry. 2012;17(11):1116-1129. doi:10.1038/mp.2011.101
Coffee and Caffeine Genetics Consortium, Cornelis MC, Byrne EM, et al. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. Mol Psychiatry. 2015;20(5):647-656. doi:10.1038/mp.2014.107
Cornelis MC, Monda KL, Yu K, et al. Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption. PLoS Genet. 2011;7(4):e1002033. doi:10.1371/journal.pgen.1002033
Sachse C, Brockmöller J, Bauer S, Roots I. Functional significance of a C-->A polymorphism in intron 1 of the cytochrome P450 CYP1A2 gene tested with caffeine. Br J Clin Pharmacol. 1999;47(4):445-449. doi:10.1046/j.1365-2125.1999.00898.x
Matthaei J, Tzvetkov M V, Strube J, et al. Heritability of Caffeine Metabolism: Environmental Effects Masking Genetic Effects on CYP1A2 Activity but Not on NAT2. Clin Pharmacol Ther. 2016;100(6):606-616. doi:10.1002/cpt.444
Di YM, Chow VD-W, Yang L-P, Zhou S-F. Structure, function, regulation and polymorphism of human cytochrome P450 2A6. Curr Drug Metab. 2009;10(7):754-780. doi:10.2174/138920009789895507
Wilke RA, Moore JH, Burmester JK. Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage. Pharmacogenet Genomics. 2005;15(6):415-421. doi:10.1097/01213011-200506000-00007
McMurray JJ V, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33(14):1787-1847. doi:10.1093/eurheartj/ehs104
Michalski SG, Bruelheide H, Durka W. Phylogenetic turnover during subtropical forest succession across environmental and phylogenetic scales. Ecol Evol. 2017;7(24):11079-11091. doi:10.1002/ece3.3564
Zhou S-F. Drugs behave as substrates, inhibitors and inducers of human cytochrome P450 3A4. Curr Drug Metab. 2008;9(4):310-322. doi:10.2174/138920008784220664
Chen Y, Goldstein JA. The transcriptional regulation of the human CYP2C genes. Curr Drug Metab. 2009;10(6):567-578. doi:10.2174/138920009789375397
Hukkanen J, Jacob P, Benowitz NL. Metabolism and disposition kinetics of nicotine. Pharmacol Rev. 2005;57(1):79-115. doi:10.1124/pr.57.1.3
McDonagh EM, Wassenaar C, David SP, et al. PharmGKB summary: very important pharmacogene information for cytochrome P-450, family 2, subfamily A, polypeptide 6. Pharmacogenet Genomics. 2012;22(9):695-708. doi:10.1097/FPC.0b013e3283540217
Ray R, Tyndale RF, Lerman C. Nicotine dependence pharmacogenetics: role of genetic variation in nicotine-metabolizing enzymes. J Neurogenet. 2009;23(3):252-261. doi:10.1080/01677060802572887
Kaida Y, Inui N, Suda T, Nakamura H, Watanabe H, Chida K. The CYP2A6*4 allele is determinant of S-1 pharmacokinetics in Japanese patients with non-small-cell lung cancer. Clin Pharmacol Ther. 2008;83(4):589-594. doi:10.1038/sj.clpt.6100484
Park SR, Kong S-Y, Nam B-H, et al. CYP2A6 and ERCC1 polymorphisms correlate with efficacy of S-1 plus cisplatin in metastatic gastric cancer patients. Br J Cancer. 2011;104(7):1126-1134. doi:10.1038/bjc.2011.24
Tanner J-A, Tyndale RF. Variation in CYP2A6 Activity and Personalized Medicine. J Pers Med. 2017;7(4). doi:10.3390/jpm7040018
Desta Z, Kreutz Y, Nguyen AT, et al. Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age. Clin Pharmacol Ther. 2011;90(5):693-700. doi:10.1038/clpt.2011.174
Tanii H, Shitara Y, Horie T. Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women. Eur J Clin Pharmacol. 2011;67(10):1017-1025. doi:10.1007/s00228-011-1042-3
Al Koudsi N, Tyndale RF. Hepatic CYP2B6 is altered by genetic, physiologic, and environmental factors but plays little role in nicotine metabolism. Xenobiotica. 2010;40(6):381-392. doi:10.3109/00498251003713958
Miksys S, Tyndale RF. The unique regulation of brain cytochrome P450 2 (CYP2) family enzymes by drugs and genetics. Drug Metab Rev. 2004;36(2):313-333. doi:10.1081/dmr-120034149
Wang H, Tompkins LM. CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Curr Drug Metab. 2008;9(7):598-610. doi:10.2174/138920008785821710
Vo TT, Varghese Gupta S. Role of Cytochrome P450 2B6 Pharmacogenomics in Determining Efavirenz-Mediated Central Nervous System Toxicity, Treatment Outcomes, and Dosage Adjustments in Patients with Human Immunodeficiency Virus Infection. Pharmacotherapy. 2016;36(12):1245-1254. doi:10.1002/phar.1852
Haas DW, Kwara A, Richardson DM, et al. Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes. J Antimicrob Chemother. 2014;69(8):2175-2182. doi:10.1093/jac/dku110
Chenoweth MJ, Tyndale RF. Pharmacogenetic Optimization of Smoking Cessation Treatment. Trends Pharmacol Sci. 2017;38(1):55-66. doi:10.1016/j.tips.2016.09.006
Läpple F, von Richter O, Fromm MF, et al. Differential expression and function of CYP2C isoforms in human intestine and liver. Pharmacogenetics. 2003;13(9):565-575. doi:10.1097/00008571-200309000-00005
Backman JT, Filppula AM, Niemi M, Neuvonen PJ. Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev. 2016;68(1):168-241. doi:10.1124/pr.115.011411
Yasar U, Lundgren S, Eliasson E, et al. Linkage between the CYP2C8 and CYP2C9 genetic polymorphisms. Biochem Biophys Res Commun. 2002;299(1):25-28. doi:10.1016/s0006-291x(02)02592-5
Kaspera R, Naraharisetti SB, Tamraz B, et al. Cerivastatin in vitro metabolism by CYP2C8 variants found in patients experiencing rhabdomyolysis. Pharmacogenet Genomics. 2010;20(10):619-629. doi:10.1097/FPC.0b013e32833ecace
Dawed AY, Donnelly L, Tavendale R, et al. CYP2C8 and SLCO1B1 Variants and Therapeutic Response to Thiazolidinediones in Patients With Type 2 Diabetes. Diabetes Care. 2016;39(11):1902-1908. doi:10.2337/dc15-2464
Barratt DT, Cox HK, Menelaou A, et al. CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients. Clin Pharmacokinet. 2017;56(8):977-985. doi:10.1007/s40262-016-0494-0
Bergmann TK, Brasch-Andersen C, Gréen H, et al. Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer. Pharmacogenomics J. 2011;11(2):113-120. doi:10.1038/tpj.2010.19
Daly AK, Rettie AE, Fowler DM, Miners JO. Pharmacogenomics of CYP2C9: Functional and Clinical Considerations. J Pers Med. 2017;8(1). doi:10.3390/jpm8010001
Baker WL, Johnson SG. Pharmacogenetics and oral antithrombotic drugs. Curr Opin Pharmacol. 2016;27:38-42. doi:10.1016/j.coph.2016.01.008
Jorgensen AL, FitzGerald RJ, Oyee J, Pirmohamed M, Williamson PR. Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis. PLoS One. 2012;7(8):e44064. doi:10.1371/journal.pone.0044064
Popp LW. [Endoscopic hernioplasty. Transcutaneous aqua dissection of the hernia sack and pre-peritoneal prosthetic coverage of the abdominal wall defect]. Chirurg. 1991;62(4):336-339.
Kirchheiner J, Brockmöller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther. 2005;77(1):1-16. doi:10.1016/j.clpt.2004.08.009
Caudle KE, Rettie AE, Whirl-Carrillo M, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Clin Pharmacol Ther. 2014;96(5):542-548. doi:10.1038/clpt.2014.159
Figueiras A, Estany-Gestal A, Aguirre C, et al. CYP2C9 variants as a risk modifier of NSAID-related gastrointestinal bleeding: a case-control study. Pharmacogenet Genomics. 2016;26(2):66-73. doi:10.1097/FPC.0000000000000186
Liang Q, Wiese RJ, Bueno OF, Dai YS, Markham BE, Molkentin JD. The transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes. Mol Cell Biol. 2001;21(21):7460-7469. doi:10.1128/MCB.21.21.7460-7469.2001
Kazui M, Nishiya Y, Ishizuka T, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38(1):92-99. doi:10.1124/dmd.109.029132
Scott SA, Sangkuhl K, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94(3):317-323. doi:10.1038/clpt.2013.105
Mega JL, Simon T, Collet J-P, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010;304(16):1821-1830. doi:10.1001/jama.2010.1543
Tornio A, Flynn R, Morant S, et al. Investigating Real-World Clopidogrel Pharmacogenetics in Stroke Using a Bioresource Linked to Electronic Medical Records. Clin Pharmacol Ther. 2018;103(2):281-286. doi:10.1002/cpt.780
Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. 2010;121(4):512-518. doi:10.1161/CIRCULATIONAHA.109.885194
Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2017;102(1):37-44. doi:10.1002/cpt.597
Gillman PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 2007;151(6):737-748. doi:10.1038/sj.bjp.0707253
Jukić MM, Haslemo T, Molden E, Ingelman-Sundberg M. Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients. Am J Psychiatry. 2018;175(5):463-470. doi:10.1176/appi.ajp.2017.17050550
Furuta T, Ohashi K, Kamata T, et al. Effect of genetic differences in omeprazole metabolism on cure rates for Helicobacter pylori infection and peptic ulcer. Ann Intern Med. 1998;129(12):1027-1030. doi:10.7326/0003-4819-129-12-199812150-00006
Zhao F, Wang J, Yang Y, et al. Effect of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple therapy for Helicobacter pylori eradication: a meta-analysis. Helicobacter. 2008;13(6):532-541. doi:10.1111/j.1523-5378.2008.00643.x
Swen JJ, Wilting I, de Goede AL, et al. Pharmacogenetics: from bench to byte. Clin Pharmacol Ther. 2008;83(5):781-787. doi:10.1038/sj.clpt.6100507
Moriyama B, Obeng AO, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. Clin Pharmacol Ther. 2017;102(1):45-51. doi:10.1002/cpt.583
He Z-X, Chen X-W, Zhou Z-W, Zhou S-F. Impact of physiological, pathological and environmental factors on the expression and activity of human cytochrome P450 2D6 and implications in precision medicine. Drug Metab Rev. 2015;47(4):470-519. doi:10.3109/03602532.2015.1101131
Pan X, Ning M, Jeong H. Transcriptional Regulation of CYP2D6 Expression. Drug Metab Dispos. 2017;45(1):42-48. doi:10.1124/dmd.116.072249
Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Klein T, Leeder JS. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med. 2017;19(1):69-76. doi:10.1038/gim.2016.80
Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008;83(2):234-242. doi:10.1038/sj.clpt.6100406
Pietarinen P, Tornio A, Niemi M. High Frequency of CYP2D6 Ultrarapid Metabolizer Genotype in the Finnish Population. Basic Clin Pharmacol Toxicol. 2016;119(3):291-296. doi:10.1111/bcpt.12590
Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014;95(4):376-382. doi:10.1038/clpt.2013.254
Somogyi AA, Coller JK, Barratt DT. Pharmacogenetics of opioid response. Clin Pharmacol Ther. 2015;97(2):125-127. doi:10.1002/cpt.23
Orliaguet G, Hamza J, Couloigner V, et al. A case of respiratory depression in a child with ultrarapid CYP2D6 metabolism after tramadol. Pediatrics. 2015;135(3):e753-5. doi:10.1542/peds.2014-2673
Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015;98(2):127-134. doi:10.1002/cpt.147
Bell GC, Caudle KE, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron. Clin Pharmacol Ther. 2017;102(2):213-218. doi:10.1002/cpt.598
Goetz MP, Sangkuhl K, Guchelaar H-J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. Clin Pharmacol Ther. 2018;103(5):770-777. doi:10.1002/cpt.1007
Werk AN, Cascorbi I. Functional gene variants of CYP3A4. Clin Pharmacol Ther. 2014;96(3):340-348. doi:10.1038/clpt.2014.129
Wang D, Guo Y, Wrighton SA, Cooke GE, Sadee W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J. 2011;11(4):274-286. doi:10.1038/tpj.2010.28
García-Martín E, Martínez C, Pizarro RM, et al. CYP3A4 variant alleles in white individuals with low CYP3A4 enzyme activity. Clin Pharmacol Ther. 2002;71(3):196-204. doi:10.1067/mcp.2002.121371
Werk AN, Lefeldt S, Bruckmueller H, et al. Identification and characterization of a defective CYP3A4 genotype in a kidney transplant patient with severely diminished tacrolimus clearance. Clin Pharmacol Ther. 2014;95(4):416-422. doi:10.1038/clpt.2013.210
Westlind-Johnsson A, Hermann R, Huennemeyer A, et al. Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity. Clin Pharmacol Ther. 2006;79(4):339-349. doi:10.1016/j.clpt.2005.11.015
Apellániz-Ruiz M, Inglada-Pérez L, Naranjo MEG, et al. High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme. Pharmacogenomics J. 2015;15(3):288-292. doi:10.1038/tpj.2014.67
Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27(4):383-391. doi:10.1038/86882
Lamba J, Hebert JM, Schuetz EG, Klein TE, Altman RB. PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenet Genomics. 2012;22(7):555-558. doi:10.1097/FPC.0b013e328351d47f
Thompson EE, Kuttab-Boulos H, Witonsky D, Yang L, Roe BA, Di Rienzo A. CYP3A variation and the evolution of salt-sensitivity variants. Am J Hum Genet. 2004;75(6):1059-1069. doi:10.1086/426406
Birdwell KA, Decker B, Barbarino JM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015;98(1):19-24. doi:10.1002/cpt.113
Willrich MA V, Hirata MH, Genvigir FD V, et al. CYP3A53A allele is associated with reduced lowering-lipid response to atorvastatin in individuals with hypercholesterolemia. Clin Chim Acta. 2008;398(1-2):15-20. doi:10.1016/j.cca.2008.07.032
Egbelakin A, Ferguson MJ, MacGill EA, et al. Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2011;56(3):361-367. doi:10.1002/pbc.22845
Garcia-Donas J, Esteban E, Leandro-García LJ, et al. Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol. 2011;12(12):1143-1150. doi:10.1016/S1470-2045(11)70266-2
