title: Pharmacogenetic approach to losartan in Marfan patients: a starting point to improve dosing regimen?
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.forename: Felicia Stefania
authors.initials: FS
authors.lastname: Falvella
authors.forename: Susan
authors.initials: S
authors.lastname: Marelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Cheli
authors.forename: Stefano
authors.initials: S
authors.lastname: Montanelli
authors.forename: Federico
authors.initials: F
authors.lastname: Viecca
authors.forename: Lucia
authors.initials: L
authors.lastname: Salvi
authors.forename: Alfio
authors.initials: A
authors.lastname: Ferrara
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
authors.forename: Giuliana
authors.initials: G
authors.lastname: Trifirò
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D065729:Cytochrome P-450 CYP2C9 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D019808:Losartan / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D008382:Marfan Syndrome / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism
chemical_list: D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D019808:Losartan