Are cytochrome P450 CYP2C8 and CYP2C9 polymorphisms associated with ibuprofen response in very preterm infants?
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.
Durrmeyer
Xavier
X
Neonatal Intensive Care Unit, CHI Créteil, France.
Hovhannisyan
Shushanik
S
Médard
Yves
Y
Jacqz-Aigrain
Evelyne
E
Decobert
Fabrice
F
Barre
Jérome
J
Alberti
Corinne
C
Aujard
Yannick
Y
Danan
Claude
C
Baud
Olivier
O
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
C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D007052:Ibuprofen
J Pediatr. 2000 Apr;136(4):454-9
10753242
Arch Biochem Biophys. 1995 Jul 10;320(2):380-9
7625847
Pediatr Res. 2005 Apr;57(4):494-9
15718364
Clin Pharmacol Ther. 2001 Oct;70(4):336-43
11673749
Acta Paediatr. 1997 Mar;86(3):289-93
9099319
Pharmacogenetics. 2001 Oct;11(7):597-607
11668219
Pharmacol Res. 2008 Jul;58(1):77-84
18694831
J Pharmacol Exp Ther. 2004 Mar;308(3):965-74
14634042
J Pediatr Surg. 1987 Dec;22(12):1171-4
3440906
Pediatrics. 2005 Jan;115(1):e44-51
15629965
Circ Res. 2001 Jan 19;88(1):44-51
11139472
Drugs Exp Clin Res. 1993;19(5):189-95
8174491
Biochem Pharmacol. 1997 Jul 1;54(1):33-41
9296349
Am J Obstet Gynecol. 1966 Jun 15;95(4):572-8
5939022
Expert Opin Drug Metab Toxicol. 2009 Jun;5(6):607-20
19422321
Am J Physiol Lung Cell Mol Physiol. 2009 Oct;297(4):L619-30
19617310
Pediatrics. 2009 Apr;123(4):1116-23
19336370
Obstet Gynecol. 2007 Feb;109(2 Pt 1):384-91
17267840
Reprod Sci. 2008 Jan;15(1):9-25
18212350
J Clin Invest. 2006 Nov;116(11):2863-5
17080192
J Pediatr Surg. 1993 Sep;28(9):1137-9
8308678
Pediatrics. 1976 Aug;58(2):167-76
951131
Mol Diagn Ther. 2006;10(1):29-40
16646575
Biochem Biophys Res Commun. 2002 Nov 22;299(1):25-8
12435384
Clin Pharmacol Ther. 2005 May;77(5):341-52
15900280
Pediatrics. 2008 May;121(5):945-56
18450898
Pediatrics. 2003 Jan;111(1):e61-6
12509596
Pediatrics. 2001 Aug;108(2):E35
11483845
Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16779-84
18922769
Am J Obstet Gynecol. 1993 Feb;168(2):572-6
8438930
Pharmacogenetics. 1997 Dec;7(6):441-52
9429229
Epidemiology. 2005 Jul;16(4):469-77
15951664
Br J Clin Pharmacol. 2005 Jan;59(1):62-9
15606441
J Clin Pharm Ther. 2005 Apr;30(2):121-32
15811164
Drug Saf. 2001;24(7):537-51
11444725
Science. 1999 Aug 20;285(5431):1276-9
10455056
Pediatrics. 2009 Feb;123(2):669-73
19171636
Clin Pharmacol Ther. 2004 Aug;76(2):119-27
15289789
N Engl J Med. 1996 Jun 20;334(25):1635-40
8628359
N Engl J Med. 2003 Sep 18;349(12):1157-67
13679531
J Pediatr. 2000 Mar;136(3):330-7
10700689
J Pediatr. 2007 Mar;150(3):216-9
17307530
Am J Physiol Renal Physiol. 2000 Dec;279(6):F965-81
11097615
Pediatrics. 1981 Dec;68(6):790-5
7322714
Arch Dis Child Fetal Neonatal Ed. 2005 Sep;90(5):F419-22
16113155
Am J Perinatol. 2003 Aug;20(6):313-20
14528401
Epidemiology. 2005 Jul;16(4):478-86
15951665