Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
European Journal of Medical Research
Published in: European Journal of Medical Research 1/2023

Open Access 01-12-2023 | Atorvastatin | Review

Association between CYP3A4/CYP3A5 genetic polymorphisms and treatment outcomes of atorvastatin worldwide: is there enough research on the Egyptian population?

Authors: Mohammed G. Maslub, Mahasen A. Radwan, Nur Aizati Athirah Daud, Abubakar Sha’aban

Published in: European Journal of Medical Research | Issue 1/2023

Login to get access

Abstract

Introduction

Atorvastatin is regarded as the most frequently prescribed statin worldwide for dyslipidemia. However, clinical response and risk of adverse effects to statin therapy are associated with genetic variations. Numerous research linked statins pharmacokinetics (PK) variations to genetic polymorphisms in cytochromes P450 (CYPs) metabolic enzymes.

Objective

This article reviews the association between CYP3A4/5 genetic variations and response to atorvastatin therapy globally, which includes atorvastatin PK, and the risk for adverse reactions, with a hint to the Egyptians.

Methods

Up to March 30, 2022, electronic medical databases like PubMed, Web of Science, MEDLINE, and Egyptian Knowledge Bank (EKB) were searched. All articles that highlighted the relationship between CYP3A4/5 genetic polymorphisms and atorvastatin efficacy/safety profile were included in this review.

Results

Initially, 492 articles were retrieved after an exhaustive search. There were 24 articles included according to the inclusion criteria. Findings of association studies of CYP3A4/5 genetic polymorphisms with response to atorvastatin varied among different ethnicities. CYP3A4*1B was associated with better therapeutic outcomes after atorvastatin therapy in Chileans and vice versa in Americans. Caucasians with myalgia while using atorvastatin were at significant risk of suffering severe muscle damage if they were carriers of CYP3A5*3/*3. As far as we can report for the Egyptian population, the impact of CYP3A4/5 genetic variations on the response to atorvastatin therapy was understudied.

Conclusion

More pharmacogenetic studies amongst diverse populations worldwide, like the Egyptian population, are necessary to detect further atorvastatin-gene interactions.

Graphical Abstract

Literature
1.
Wake DT, Ilbawi N, Dunnenberger HM, Hulick PJ. Pharmacogenomics: prescribing precisely. Med Clin North Am. 2019;103:977–90.PubMedCrossRef
2.
3.
Gray K, Adhikary SD, Janicki P. Pharmacogenomics of analgesics in anesthesia practice: A current update of literature. J Anaesthesiol Clin Pharmacol. 2018;34:155–60.PubMedPubMedCentralCrossRef
4.
Lynch T, Price A. The effect of cytochrome p450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76:391–6.PubMed
5.
Sarlis NJ, Gourgiotis L. Hormonal effects on drug metabolism through the CYP system: Perspectives on their potential significance in the era of pharmacogenomics. Curr Drug Targets Immune Endocr Metabol Disord. 2005;5:439–48.PubMedCrossRef
6.
7.
Agache I, Akdis CA. Precision medicine and phenotypes, endotypes, genotypes, regiotypes, and theratypes of allergic diseases. J Clin Invest. 2019;129:1493–503.PubMedPubMedCentralCrossRef
8.
Licata A, Giammanco A, Minissale MG, Pagano S, Petta S, Averna M. Liver and statins: a critical appraisal of the evidence. Curr Med Chem. 2018;25:5835–46.PubMedCrossRef
9.
Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA. 2001;286:2270–9.PubMedCrossRef
10.
Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians Africans and their descendants. Pharmacogenomics. 2002;3:229–43.PubMedCrossRef
11.
Special report: Genotyping for cytochrome p450 polymorphisms to determine drug-metabolizer status. Technol Eval Cent Assess Program Exec Summ 2004; 19: 1–2.
12.
Willrich MA, Rodrigues AC, Cerda A, Genvigir FD, Arazi SS, Dorea EL, Bernik MM, Bertolami MC, Faludi A, Largura A, Baudhuin LM, Bryant SC, Hirata MH, Hirata RD. Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients. Clin Chim Acta. 2013;421:157–63.PubMedCrossRef
13.
14.
Parke-Davis MP. Product information. Lipitor (atorvastatin). HIGHLIGHTS OF PRESCRIBING INFORMATION of ATORVASTATIN CALCIUM 2009.
15.
Dagli-Hernandez C, Zhou Y, Lauschke VM, Genvigir FDV, Hirata TDC, Hirata MH, Hirata RDC. Pharmacogenomics of statins: lipid response and other outcomes in Brazilian cohorts. Pharmacol Rep. 2022;74:47–66.PubMedCrossRef
16.
Kitzmiller JP, Mikulik EB, Dauki AM, Murkherjee C, Luzum JA. Pharmacogenomics of statins: understanding susceptibility to adverse effects. Pharmgenomics Pers Med. 2016;9:97–106.PubMedPubMedCentral
17.
Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111–88.PubMedCrossRef
18.
Taha HSED, Badran HM, Kandil H, Farag N, Oraby A, El Sharkawy M, Shokry K, Fawzy F, Mahrous H, Bahgat J, Samy M, Shaker MM. Egyptian practical guidance in lipid management 2020. Egypt Heart J. 2021;73:17.PubMedPubMedCentralCrossRef
19.
Reda A, Abdel-Rehim AA, Etman A, Afifi OS. Centralized pan-Middle East survey on the under-treatment of hypercholesterolemia: results from the CEPHEUS study in Egypt. Cardiol Ther. 2014;3:27–40.PubMedPubMedCentralCrossRef
20.
Farag ES, Reda A, Farag N, Salama S, Elbahry A, Sanad O, Abdou W, El-Kersh A. The Egyptian cardiovascular risk factors project, phase (ii) results: a multicenter observational study of the pattern of risk factor profile in Egyptian patients with acute coronary syndrome. Atherosclerosis. 2017;263: e159.CrossRef
21.
Rosales A, Alvear M, Cuevas A, Saavedra N, Zambrano T, Salazar LA. Identification of pharmacogenetic predictors of lipid-lowering response to atorvastatin in Chilean subjects with hypercholesterolemia. Clin Chim Acta. 2012;413:495–501.PubMedCrossRef
22.
Sobhy M, El Etriby A, El Nashar A, Wajih S, Horack M, Brudi P, Lautsch D, Ambegaonkar B, Vyas A, Gitt AK. Prevalence of lipid abnormalities and cholesterol target value attainment in Egyptian patients presenting with an acute coronary syndrome. Egypt Heart J. 2018;70:129–34.PubMedPubMedCentralCrossRef
23.
24.
Shitara Y, Sugiyama Y. Pharmacokinetic and pharmacodynamic alterations of 3-hydroxy-3-methylglutaryl coenzyme a (HMG-COA) reductase inhibitors: drug-drug interactions and interindividual differences in transporter and metabolic enzyme functions. Pharmacol Ther. 2006;112:71–105.PubMedCrossRef
25.
Kivistö KT, Niemi M, Schaeffeler E, Pitkälä K, Tilvis R, Fromm MF, Schwab M, Eichelbaum M, Strandberg T. Lipid-lowering response to statins is affected by CYP3A5 polymorphism. Pharmacogenetics. 2004;14:523–5.PubMedCrossRef
26.
Zubiaur P, Benedicto MD, Villapalos-García G, Navares-Gómez M, Mejía-Abril G, Román M, Martín-Vílchez S, Ochoa D, Abad-Santos F. SLCO1B1 phenotype and CYP3A5 polymorphism significantly affect atorvastatin bioavailability. J Pers Med. 2021;11:204.PubMedPubMedCentralCrossRef
27.
He BX, Shi L, Qiu J, Zeng XH, Zhao SJ. The effect of CYP3A4*1g allele on the pharmacokinetics of atorvastatin in Chinese Han patients with coronary heart disease. J Clin Pharmacol. 2014;54:462–7.PubMedCrossRef
28.
Park JE, Kim KB, Bae SK, Moon BS, Liu KH, Shin JG. Contribution of cytochrome p450 3A4 and 3A5 to the metabolism of atorvastatin. Xenobiotica. 2008;38:1240–51.PubMedCrossRef
29.
Maekawa K, Harakawa N, Yoshimura T, Kim S-R, Fujimura Y, Aohara F, Sai K, Katori N, Tohkin M, Naito M, Hasegawa R, Okuda H, Sawada J-I, Niwa T, Saito Y. CYP3A4*16 and CYP3A4*18 alleles found in east Asians exhibit differential catalytic activities for seven CYP3A4 substrate drugs. Drug Metab Dispos. 2010;38:2100–4.PubMedCrossRef
30.
Jani AJ, Rathnam S, Mehta AA. Phenotyping of cytochrome P450 3A enzyme in Gujarat population. Drug Metab Lett. 2008;2:5–10.PubMedCrossRef
31.
Poduri A, Khullar M, Bahl A, Sehrawat BS, Sharma Y, Talwar KK. Common variants of HMGCR, CETP, APOAI, ABCB1, CYP3A4, and CYP7A1 genes as predictors of lipid-lowering response to atorvastatin therapy. DNA Cell Biol. 2010;29:629–37.PubMedCrossRef
32.
Gao Y, Zhang LR, Fu Q. CYP3A4*1g polymorphism is associated with lipid-lowering efficacy of atorvastatin but not of simvastatin. Eur J Clin Pharmacol. 2008;64:877–82.PubMedCrossRef
33.
Peng C, Ding Y, Yi X, Shen Y, Dong Z, Cao L, Li Q, Ren H, He L, Zhou D, Chen X. Polymorphisms in CYP450 genes and the therapeutic effect of atorvastatin on ischemic stroke: A retrospective cohort study in Chinese population. Clin Ther. 2018;40:469-477.e462.PubMedCrossRef
34.
Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia. Am J Cardiol. 2004;93:104–7.PubMedCrossRef
35.
Willrich MA, Hirata MH, Hirata RD. Statin regulation of CYP3A4 and CYP3A5 expression. Pharmacogenomics. 2009;10:1017–24.PubMedCrossRef
36.
Kadam P, Ashavaid TF, Ponde CK, Rajani RM. Genetic determinants of lipid-lowering response to atorvastatin therapy in an Indian population. J Clin Pharm Ther. 2016;41:329–33.PubMedCrossRef
37.
Klein K, Thomas M, Winter S, Nussler AK, Niemi M, Schwab M, Zanger UM. Ppara: a novel genetic determinant of CYP3A4 in vitro and in vivo. Clin Pharmacol Ther. 2012;91:1044–52.PubMedCrossRef
38.
Kolovou G, Kolovou V, Ragia G, Mihas C, Diakoumakou O, Vasiliadis I, Mavrogeni S, Vartela V, Manolopoulos VG. CYP3A5 genotyping for assessing the efficacy of treatment with simvastatin and atorvastatin. Genet Mol Biol. 2015;38:129–37.PubMedPubMedCentralCrossRef
39.
Willrich MAV, Hirata MH, Genvigir FDV, Arazi SS, Rebecchi IMM, Rodrigues AC, Bernik MMS, Dorea EL, Bertolami MC, Faludi AA, Hirata RDC. CYP3A5*3A allele is associated with reduced lowering-lipid response to atorvastatin in individuals with hypercholesterolemia. Clin Chim Acta. 2008;398:15–20.PubMedCrossRef
40.
Vrablik M, Zlatohlavek L, Stulc T, Adamkova V, Prusikova M, Schwarzova L, Hubacek JA, Ceska R. Statin-associated myopathy: From genetic predisposition to clinical management. Physiol Res. 2014;63:S327-334.PubMedCrossRef
41.
Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH. Influence of genetic variation in CYP3A4 and ABCB1 on dose decrease or switching during simvastatin and atorvastatin therapy. Pharmacoepidemiol Drug Saf. 2010;19:75–81.PubMedCrossRef
42.
Xia B, Li Y, Zhang Y, Xue M, Li X, Xu P, Xia T, Chen S. UHPLC-MS/MS method for determination of atorvastatin calcium in human plasma: Application to a pharmacokinetic study based on healthy volunteers with specific genotype. J Pharm Biomed Anal. 2018;160:428–35.PubMedCrossRef
43.
Liu J-E, Ren B, Tang L, Tang Q-J, Liu X-Y, Li X, Bai X, Zhong W-P, Meng J-X, Lin H-M, Wu H, Chen J-Y, Zhong S-L. The independent contribution of miRNAs to the missing heritability in CYP3A4/5 functionality and the metabolism of atorvastatin. Sci Rep. 2016;6:26544.PubMedPubMedCentralCrossRef
44.
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;15:415–21.PubMedCrossRef
45.
Benes LB, Bassi NS, Davidson MH. The risk of hepatotoxicity, new onset diabetes and rhabdomyolysis in the era of high-intensity statin therapy: Does statin type matter? Prog Cardiovasc Dis. 2016;59:145–52.PubMedCrossRef
46.
Ahangari N, Doosti M, Ghayour Mobarhan M, Sahebkar A, Ferns GA, Pasdar A. Personalised medicine in hypercholesterolaemia: The role of pharmacogenetics in statin therapy. Ann Med. 2020;52:462–70.PubMedPubMedCentralCrossRef
47.
DeGorter MK, Tirona RG, Schwarz UI, Choi YH, Dresser GK, Suskin N, Myers K, Zou G, Iwuchukwu O, Wei WQ, Wilke RA, Hegele RA, Kim RB. Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care. Circ Cardiovasc Genet. 2013;6:400–8.PubMedPubMedCentralCrossRef
48.
Voora D, Shah SH, Spasojevic I, Ali S, Reed CR, Salisbury BA, Ginsburg GS. The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol. 2009;54:1609–16.PubMedPubMedCentralCrossRef
49.
Liu JE, Liu XY, Chen S, Zhang Y, Cai LY, Yang M, Lai WH, Ren B, Zhong SL. SLCO1B1 521T > C polymorphism associated with rosuvastatin-induced myotoxicity in Chinese coronary artery disease patients: a nested case-control study. Eur J Clin Pharmacol. 2017;73:1409–16.PubMedCrossRef
50.
Frudakis TN, Thomas MJ, Ginjupalli SN, Handelin B, Gabriel R, Gomez HJ. CYP2D6*4 polymorphism is associated with statin-induced muscle effects. Pharmacogenet Genomics. 2007;17:695–707.PubMedCrossRef
51.
Wohlers I, Künstner A, Munz M, Olbrich M, Fähnrich A, Calonga-Solís V, Ma C, Hirose M, El-Mosallamy S, Salama M, Busch H, Ibrahim S. An integrated personal and population-based Egyptian genome reference. Nat Commun. 2020;11:4719.PubMedPubMedCentralCrossRef
52.
Mutawi TM, Zedan MM, Yahya RS, Zakria MM, El-Sawi MR, Gaedigk A. Genetic variability of CYP2D6, CYP3A4 and CYP3A5 among the Egyptian population. Pharmacogenomics. 2021;22:323–34.PubMedCrossRef
53.
Sharaki O, Zeid M, Moez P, Zakaria NH, Nassar E. Impact of CYP3A4 and MDR1 gene (G2677T) polymorphisms on dose requirement of the cyclosporine in renal transplant Egyptian recipients. Mol Biol Rep. 2015;42:105–17.PubMedCrossRef
54.
Abd El Wahab N, Shafik NF, Shafik RE, Taha SA, Shafik HE, Darwish AD. Association of CYP3A5*3 and CYP1A1*2C polymorphism with development of acute myeloid leukemia in Egyptian patients. Asian Pac J Cancer Prev. 2017;18:747–52.PubMed
55.
Mendrinou E, Mashaly ME, Al Okily AM, Mohamed ME, Refaie AF, Elsawy EM, Saleh HH, Sheashaa H, Patrinos GP. CYP3A5 gene-guided tacrolimus treatment of living-donor Egyptian kidney transplanted patients. Front Pharmacol. 2020;11:1218.PubMedPubMedCentralCrossRef
56.
Bedewy AML, El-Maghraby SM. Do SLCO1B3 (T334G) and CYP3A5*3 polymorphisms affect response in Egyptian chronic myeloid leukemia patients receiving imatinib therapy? Hematology. 2013;18:211–6.PubMedCrossRef
57.
Abo El Fotoh WM, Abd El Naby SA, Habib MS, Kasemy ZA. The potential implication of SCN1A and CYP3A5 genetic variants on antiepileptic drug resistance among Egyptian epileptic children. Seizure. 2016;41:75–80.PubMedCrossRef
Metadata
Title
Association between CYP3A4/CYP3A5 genetic polymorphisms and treatment outcomes of atorvastatin worldwide: is there enough research on the Egyptian population?
Authors
Mohammed G. Maslub
Mahasen A. Radwan
Nur Aizati Athirah Daud
Abubakar Sha’aban
Publication date
01-12-2023
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2023
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-023-01038-1

Other articles of this Issue 1/2023

European Journal of Medical Research 1/2023 Go to the issue

Research

Sex-specific association between carotid atherosclerosis and fundus arteriosclerosis in a Chinese population: a retrospective cross-sectional study

Research

Validity of distal radius fracture diagnoses in the Swedish National Patient Register

Research

PCMT1 is a potential target related to tumor progression and immune infiltration in liver cancer

Research

Role of hyperbaric oxygen therapy in PDGF-BB-mediated astrogliosis in traumatic brain injury rats associated with ERK1/2 signaling pathway inhibition

Research

Activating transcription factor (ATF) 6 upregulates cystathionine β synthetase (CBS) expression and hydrogen sulfide (H2S) synthesis to ameliorate liver metabolic damage

Research

Different expression and prognostic value of troponin in ischemic cardiomyopathy and non-ischemic dilated cardiomyopathy