Pharmacogenetic approach to losartan in Marfan patients: a starting point to improve dosing regimen?
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Felicia Stefania Falvella
Abstract
Background:
Losartan is under evaluation for managing Marfan patients with aortic root dilatation. Cytochrome P450 (CYP) enzymes convert losartan to E3174 active metabolite. The aim of this study is to describe the distribution of CYP2C9*2, CYP2C9*3, CYP3A4*22 and CYP3A5*3 defective alleles, according to losartan tolerance in paediatric Marfan patients.
Methods:
We genotyped 53 paediatric Marfan patients treated with losartan. The rate of aortic root dilatation was evaluated using the delta z-score variation. Differences in tolerated losartan daily doses with respect to CYP metabolic classes were assessed through the Kruskal-Wallis test.
Results:
The losartan daily dose spans from 0.16 to 2.50 mg/kg (median 1.10 mg/kg). As we expect from the pharmacokinetics pathway, we observe highest tolerated dose in CYP2C9 poor metabolisers (median 1.50 mg/kg, interquartile range 1.08–1.67 mg/kg); however, this difference is not statistically significant.
Conclusions:
The optimal dose of angiotensin receptor blocker is not known, and no data are available about losartan pharmacogenetic profile in Marfan syndrome; we have proposed a strategy to tackle this issue based on evaluating the major genetic polymorphisms involved in the losartan conversion into active carboxylic acid metabolite. Further studies are needed to support the use of genetic polymorphisms as predictors of the right dose of losartan.
Acknowledgments
The authors are grateful to the university student Gaetano Raffaella for her essential contribution in pharmacogenetic analysis and in the revision of the manuscript.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None.
Employment or leadership: None.
Honorarium: None.
Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Judge DP, Dietz HC. Marfan’s syndrome. Lancet 2005;366: 1965–76.10.1016/S0140-6736(05)67789-6Suche in Google Scholar
2. Dean JC. Marfan syndrome: clinical diagnosis and management. Eur J Hum Genet 2007;15:724–33.10.1038/sj.ejhg.5201851Suche in Google Scholar
3. Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010;47:476–85.10.1136/jmg.2009.072785Suche in Google Scholar
4. Matt P, Schoenhoff F, Habashi J, Holm T, Van Erp C, Loch D, et al. Circulating transforming growth factor-beta in Marfan syndrome. Circulation 2009;120:526–32.10.1161/CIRCULATIONAHA.108.841981Suche in Google Scholar
5. Dietz HC. TGF-beta in the pathogenesis and prevention of disease: a matter of aneurysmic proportions. J Clin Invest 2010;120:403–7.10.1172/JCI42014Suche in Google Scholar
6. Chung AW, Au Yeung K, Cortes SF, Sandor GG, Judge DP, Dietz HC, et al. Endothelial dysfunction and compromised eNOS/Akt signaling in the thoracic aorta during the progression of Marfan syndrome. Br J Pharmacol 2007;150:1075–83.10.1038/sj.bjp.0707181Suche in Google Scholar
7. De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62:417–26.10.1002/(SICI)1096-8628(19960424)62:4<417::AID-AJMG15>3.0.CO;2-RSuche in Google Scholar
8. Ramirez F, Dietz HC. Marfan syndrome: from molecular pathogenesis to clinical treatment. Curr Opin Genet Dev 2007;17: 252–8.10.1016/j.gde.2007.04.006Suche in Google Scholar
9. Li-Wan-Po A, Loeys B, Farndon P, Latham D, Bradley C. Preventing the aortic complications of Marfan syndrome: a case-example of translational genomic medicine. Br J Clin Pharmacol 2011;72:6–17.10.1111/j.1365-2125.2011.03929.xSuche in Google Scholar
10. Sengle G, Sakai LY. The fibrillin microfibril scaffold: a niche for growth factors and mechanosensation? Matrix Biol 2015;47: 3–12.10.1016/j.matbio.2015.05.002Suche in Google Scholar
11. Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term beta-adrenergic blockade in Marfan’s syndrome. N Engl J Med 1994;330:1335–41.10.1056/NEJM199405123301902Suche in Google Scholar PubMed
12. Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 2006;312: 117–21.10.1126/science.1124287Suche in Google Scholar PubMed PubMed Central
13. Lacro RV, Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, et al. Atenolol versus losartan in children and young adults with Marfan’s syndrome. N Engl J Med 2014;371:2061–71.10.1056/NEJMoa1404731Suche in Google Scholar PubMed PubMed Central
14. Forteza A, Evangelista A, Sánchez V, Teixidó-Turà G, Sanz P, Gutiérrez L, et al. Efficacy of losartan vs. atenolol for the prevention of aortic dilation in Marfan syndrome: a randomized clinical trial. Eur Heart J 2016;37:978–85.10.1093/eurheartj/ehv575Suche in Google Scholar PubMed
15. Brooke BS, Habashi JP, Judge DP, Patel N, Loeys B, Dietz HC 3rd. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med 2008;358:2787–95.10.1056/NEJMoa0706585Suche in Google Scholar PubMed PubMed Central
16. Groenink M, den Hartog AW, Franken R, Radonic T, de Waard V, Timmermans J, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J 2013;34:3491–500.10.1093/eurheartj/eht334Suche in Google Scholar PubMed
17. Milleron O, Arnoult F, Ropers J, Aegerter P, Detaint D, Delorme G, et al. Marfan Sartan: a randomized, double-blind, placebo-controlled trial. Eur Heart J 2015;36:2160–6.10.1093/eurheartj/ehv151Suche in Google Scholar PubMed
18. Franken R, den Hartog AW, Radonic T, Micha D, Maugeri A, van Dijk FS, et al. Beneficial outcome of losartan therapy depends on type of FBN1 mutation in Marfan syndrome. Circ Cardiovasc Genet 2015;8:383–8.10.1161/CIRCGENETICS.114.000950Suche in Google Scholar PubMed
19. Pitcher A, Emberson J, Lacro RV, Sleeper LA, Stylianou M, Mahony L, et al. Design and rationale of a prospective, collaborative meta-analysis of all randomized controlled trials of angiotensin receptor antagonists in Marfan syndrome, based on individual patient data: a report from the Marfan Treatment Trialists’ Collaboration. Am Heart J 2015;169:605–12.10.1016/j.ahj.2015.01.011Suche in Google Scholar PubMed PubMed Central
20. Stearns RA, Chakravarty PK, Chen R, Chiu SH. Biotransformation of losartan to its active carboxylic acid metabolite in human liver microsomes. Role of cytochrome P4502C and 3A subfamily members. Drug Metab Dispos 1995;23:207–15.10.1016/S0090-9556(25)06520-1Suche in Google Scholar
21. Sica DA, Gehr TW, Ghosh S. Clinical pharmacokinetics of losartan. Clin Pharmacokinet 2005;44:797–814.10.2165/00003088-200544080-00003Suche in Google Scholar PubMed
22. Bae JW, Choi CI, Lee HI, Lee YJ, Jang CG, Lee SY. Effects of CYP2C9*1/*3 and *1/*13 on the pharmacokinetics of losartan and its active metabolite E-3174. Int J Clin Pharmacol Ther 2012;50:683–9.10.5414/CP201467Suche in Google Scholar
23. Yasar U, Tybring G, Hidestrand M, Oscarson M, Ingelman-Sundberg M, Dahl ML, et al. Role of CYP2C9 polymorphism in losartan oxidation. Drug Metab Dispos 2001;29:1051–6.Suche in Google Scholar
24. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001;27:383–91.10.1038/86882Suche in Google Scholar
25. 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;11:274–86.10.1038/tpj.2010.28Suche in Google Scholar
26. Gautier M, Detaint D, Fermanian C, Aegerter P, Delorme G, Arnoult F, et al. Nomograms for aortic root diameters in children using two-dimensional echocardiography. Am J Cardiol 2010;105:888–94.10.1016/j.amjcard.2009.11.040Suche in Google Scholar
27. Goa KL, Wagstaff AJ. Losartan potassium: a review of its pharmacology, clinical efficacy and tolerability in the management of hypertension. Drugs 1996;51:820–45.10.2165/00003495-199651050-00008Suche in Google Scholar
28. Carswell CI, Goa KL. Losartan in diabetic nephropathy. Drugs 2003;63:407–14;discussion 415–16.10.2165/00003495-200363040-00006Suche in Google Scholar
29. Rodriguez S, Gaunt TR, Day IN. Hardy-Weinberg equilibrium testing of biological ascertainment for Mendelian randomization studies. Am J Epidemiol 2009;169:505–14.10.1093/aje/kwn359Suche in Google Scholar
30. Elens L, van Gelder T, Hesselink DA, Haufroid V, van Schaik RH. CYP3A4*22: promising newly identified CYP3A4 variant allele for personalizing pharmacotherapy. Pharmacogenomics 2013;14:47–62.10.2217/pgs.12.187Suche in Google Scholar
31. Lo MW, Goldberg MR, McCrea JB, Lu H, Furtek CI, Bjornsson TD. Pharmacokinetics of losartan, an angiotensin II receptor antagonist, and its active metabolite EXP3174 in humans. Clin Pharmacol Ther 1995;58:641–9.10.1016/0009-9236(95)90020-9Suche in Google Scholar
32. Li Z, Wang G, Wang LS, Zhang W, Tan ZR, Fan L, et al. Effects of the CYP2C9*13 allele on the pharmacokinetics of losartan in healthy male subjects. Xenobiotica 2009;39:788–93.10.1080/00498250903134435Suche in Google Scholar PubMed
33. Dorado P, Gallego A, Peñas-LLedó E, Terán E, LLerena A. Relationship between the CYP2C9 IVS8-109A>T polymorphism and high losartan hydroxylation in healthy Ecuadorian volunteers. Pharmacogenomics 2014;15:1417–21.10.2217/pgs.14.85Suche in Google Scholar PubMed
34. Hatta FH, Teh LK, Hellden A, Hellgren KE, Roh HK, Salleh MZ, et al. Search for the molecular basis of ultra-rapid CYP2C9-catalysed metabolism: relationship between SNP IVS8-109A>T and the losartan metabolism phenotype in Swedes. Eur J Clin Pharmacol 2012;68:1033–42.10.1007/s00228-012-1210-0Suche in Google Scholar PubMed
35. Singh MN, Lacro RV. Recent clinical drug trials evidence in Marfan syndrome and clinical implications. Can J Cardiol 2016;32:66–77.10.1016/j.cjca.2015.11.003Suche in Google Scholar PubMed
©2016 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Review
- Pharmacogenomics in pain treatment
- Original Articles
- Association study of DRD2 A2/A1, DRD3 Ser9Gly, DβH −1021C>T, OPRM1 A118G and GRIK1 rs2832407C>A polymorphisms with alcohol dependence
- Medication therapy management (MTM): an innovative approach to improve medication adherence in diabetics
- Pharmacogenetic approach to losartan in Marfan patients: a starting point to improve dosing regimen?
- Altered pharmacokinetics of rosiglitazone in a mouse model of non-alcoholic fatty liver disease
- The impact of CYP4F2, ABCB1, and GGCX polymorphisms on bleeding episodes associated with acenocoumarol in Russian patients with atrial fibrillation
Artikel in diesem Heft
- Frontmatter
- Review
- Pharmacogenomics in pain treatment
- Original Articles
- Association study of DRD2 A2/A1, DRD3 Ser9Gly, DβH −1021C>T, OPRM1 A118G and GRIK1 rs2832407C>A polymorphisms with alcohol dependence
- Medication therapy management (MTM): an innovative approach to improve medication adherence in diabetics
- Pharmacogenetic approach to losartan in Marfan patients: a starting point to improve dosing regimen?
- Altered pharmacokinetics of rosiglitazone in a mouse model of non-alcoholic fatty liver disease
- The impact of CYP4F2, ABCB1, and GGCX polymorphisms on bleeding episodes associated with acenocoumarol in Russian patients with atrial fibrillation
