title: Are cytochrome P450 CYP2C8 and CYP2C9 polymorphisms associated with ibuprofen response in very preterm infants?
abstract: BACKGROUND
  Patent ductus arteriosus (PDA) in extremely preterm infants remains a challenging condition with conflicting treatment strategies. Ibuprofen is currently used to treat PDA with ductal closure failure rate up to 40%. We test the hypothesis that cytochrome P450 CYP2C8/2C9 polymorphisms may predict ibuprofen response.
  
  
  RESULTS
  We studied extremely preterm neonates with haemodynamically significant PDA and treated with ibuprofen. One or two variant CYP2C8 and/or 2C9 alleles were found in 17% of the population, most of them were from Caucasian ethnicity (67-74%). Response to ibuprofen and clinical course of infants carrying variants CYP2C8 and CYP2C9 were similar. Comparing infants with wild type or variant CYP2C8 and CYP2C9 genotypes, response rate to ibuprofen was significantly higher in wild type than in mutated carriers in univariate analysis (73% versus 52%, p = 0.04). Comparing responders (ductus closure; n = 75) and non-responders (surgical ligation; n = 36), the only two factors significantly associated with the response to ibuprofen using multivariate analysis were higher gestational age and non Caucasian ethnicity but not CYP2C polymorphism.
  
  
  CONCLUSIONS
  CYP2C polymorphism was not associated with PDA response to ibuprofen and this factor appears not appropriate to optimize the ductal closure rate by modulating ibuprofen dosing strategy. This study points out the role for ethnicity in the interindividual variability of response to ibuprofen in extremely preterm infants.
authors.affiliation: Neonatal Intensive Care Unit, CHI Créteil, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Durrmeyer
authors.forename: Shushanik
authors.initials: S
authors.lastname: Hovhannisyan
authors.forename: Yves
authors.initials: Y
authors.lastname: Médard
authors.forename: Evelyne
authors.initials: E
authors.lastname: Jacqz-Aigrain
authors.forename: Fabrice
authors.initials: F
authors.lastname: Decobert
authors.forename: Jérome
authors.initials: J
authors.lastname: Barre
authors.forename: Corinne
authors.initials: C
authors.lastname: Alberti
authors.forename: Yannick
authors.initials: Y
authors.lastname: Aujard
authors.forename: Claude
authors.initials: C
authors.lastname: Danan
authors.forename: Olivier
authors.initials: O
authors.lastname: Baud
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065727:Cytochrome P-450 CYP2C8; D065729:Cytochrome P-450 CYP2C9; D004374:Ductus Arteriosus, Patent / Q000188:drug therapy / Q000235:genetics / Q000628:therapy; D005260:Female; D005838:Genotype; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology* / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D047928:Premature Birth; D016896:Treatment Outcome
chemical_list: C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D007052:Ibuprofen
references.citation: J Pediatr. 2000 Apr;136(4):454-9
references.pmid: 10753242
references.citation: Arch Biochem Biophys. 1995 Jul 10;320(2):380-9
references.pmid: 7625847
references.citation: Pediatr Res. 2005 Apr;57(4):494-9
references.pmid: 15718364
references.citation: Clin Pharmacol Ther. 2001 Oct;70(4):336-43
references.pmid: 11673749
references.citation: Acta Paediatr. 1997 Mar;86(3):289-93
references.pmid: 9099319
references.citation: Pharmacogenetics. 2001 Oct;11(7):597-607
references.pmid: 11668219
references.citation: Pharmacol Res. 2008 Jul;58(1):77-84
references.pmid: 18694831
references.citation: J Pharmacol Exp Ther. 2004 Mar;308(3):965-74
references.pmid: 14634042
references.citation: J Pediatr Surg. 1987 Dec;22(12):1171-4
references.pmid: 3440906
references.citation: Pediatrics. 2005 Jan;115(1):e44-51
references.pmid: 15629965
references.citation: Circ Res. 2001 Jan 19;88(1):44-51
references.pmid: 11139472
references.citation: Drugs Exp Clin Res. 1993;19(5):189-95
references.pmid: 8174491
references.citation: Biochem Pharmacol. 1997 Jul 1;54(1):33-41
references.pmid: 9296349
references.citation: Am J Obstet Gynecol. 1966 Jun 15;95(4):572-8
references.pmid: 5939022
references.citation: Expert Opin Drug Metab Toxicol. 2009 Jun;5(6):607-20
references.pmid: 19422321
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Oct;297(4):L619-30
references.pmid: 19617310
references.citation: Pediatrics. 2009 Apr;123(4):1116-23
references.pmid: 19336370
references.citation: Obstet Gynecol. 2007 Feb;109(2 Pt 1):384-91
references.pmid: 17267840
references.citation: Reprod Sci. 2008 Jan;15(1):9-25
references.pmid: 18212350
references.citation: J Clin Invest. 2006 Nov;116(11):2863-5
references.pmid: 17080192
references.citation: J Pediatr Surg. 1993 Sep;28(9):1137-9
references.pmid: 8308678
references.citation: Pediatrics. 1976 Aug;58(2):167-76
references.pmid: 951131
references.citation: Mol Diagn Ther. 2006;10(1):29-40
references.pmid: 16646575
references.citation: Biochem Biophys Res Commun. 2002 Nov 22;299(1):25-8
references.pmid: 12435384
references.citation: Clin Pharmacol Ther. 2005 May;77(5):341-52
references.pmid: 15900280
references.citation: Pediatrics. 2008 May;121(5):945-56
references.pmid: 18450898
references.citation: Pediatrics. 2003 Jan;111(1):e61-6
references.pmid: 12509596
references.citation: Pediatrics. 2001 Aug;108(2):E35
references.pmid: 11483845
references.citation: Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16779-84
references.pmid: 18922769
references.citation: Am J Obstet Gynecol. 1993 Feb;168(2):572-6
references.pmid: 8438930
references.citation: Pharmacogenetics. 1997 Dec;7(6):441-52
references.pmid: 9429229
references.citation: Epidemiology. 2005 Jul;16(4):469-77
references.pmid: 15951664
references.citation: Br J Clin Pharmacol. 2005 Jan;59(1):62-9
references.pmid: 15606441
references.citation: J Clin Pharm Ther. 2005 Apr;30(2):121-32
references.pmid: 15811164
references.citation: Drug Saf. 2001;24(7):537-51
references.pmid: 11444725
references.citation: Science. 1999 Aug 20;285(5431):1276-9
references.pmid: 10455056
references.citation: Pediatrics. 2009 Feb;123(2):669-73
references.pmid: 19171636
references.citation: Clin Pharmacol Ther. 2004 Aug;76(2):119-27
references.pmid: 15289789
references.citation: N Engl J Med. 1996 Jun 20;334(25):1635-40
references.pmid: 8628359
references.citation: N Engl J Med. 2003 Sep 18;349(12):1157-67
references.pmid: 13679531
references.citation: J Pediatr. 2000 Mar;136(3):330-7
references.pmid: 10700689
references.citation: J Pediatr. 2007 Mar;150(3):216-9
references.pmid: 17307530
references.citation: Am J Physiol Renal Physiol. 2000 Dec;279(6):F965-81
references.pmid: 11097615
references.citation: Pediatrics. 1981 Dec;68(6):790-5
references.pmid: 7322714
references.citation: Arch Dis Child Fetal Neonatal Ed. 2005 Sep;90(5):F419-22
references.pmid: 16113155
references.citation: Am J Perinatol. 2003 Aug;20(6):313-20
references.pmid: 14528401
references.citation: Epidemiology. 2005 Jul;16(4):478-86
references.pmid: 15951665