title: Evaluation of lansoprazole as a probe for assessing cytochrome P450 2C19 activity and genotype-phenotype correlation in childhood.
abstract: OBJECTIVE
  Lansoprazole, a cytochrome P450 2C19 (CYP2C19) substrate, has been widely used in children to manage acid-related diseases. CYP2C19 exhibits marked genetic polymorphisms, and distribution of these polymorphisms varies among different ethnic groups. There is limited data regarding the use of probe drugs for determining CYP2C19 activity in children. The aim of this study was to evaluate lansoprazole as an in vivo phenotyping probe for assessing CYP2C19 activity in children.
  
  
  METHODS
  The CYP2C19*2, *3, and *17 variants were determined in 244 children. Three hours after a single oral dose of lansoprazole (n = 94) or omeprazole (n = 19), plasma lansoprazole and 5-hydroxy lansoprazole or omeprazole and 5-hydroxy omeprazole concentrations were analyzed by high-performance liquid chromatography.
  
  
  RESULTS
  The CYP2C19*17 was the most frequent variant allele (24.4%). The group of patients with CYP2C19*17*17 genotype had a 70% lower (p < 0.05) mean lansoprazole plasma concentration compared with the CYP2C19*1*1 genotype group, whereas the CYP2C19*2*2 group had 6.9-fold higher (p < 0.01) mean lansoprazole plasma concentration. Lansoprazole metabolic ratios (lansoprazole/5-hydroxy-lansoprazole) were found to be significantly lower in the *17*17 [mean ± standard deviation (SD); 2.8 ± 2.1] group and higher in the *2*2 group (63.5 ± 12.2) compared with that of the *1*1 genotype group (6.1 ± 4.5).
  
  
  CONCLUSIONS
  According to our results from a Turkish pediatric population, lansoprazole is a suitable probe drug for phenotyping CYP2C19. The CYP2C19*2 and *17 variants should be taken into consideration in predicting the clinical outcome of therapy with lansoprazole in the pediatric population.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Hacettepe University, Sihhiye, Ankara, Turkey.
authors.forename: Ersin
authors.initials: E
authors.lastname: Gumus
authors.forename: Ozgur
authors.initials: O
authors.lastname: Karaca
authors.forename: Melih O
authors.initials: MO
authors.lastname: Babaoglu
authors.forename: Gökhan
authors.initials: G
authors.lastname: Baysoy
authors.forename: Necati
authors.initials: N
authors.lastname: Balamtekin
authors.forename: Hulya
authors.initials: H
authors.lastname: Demir
authors.forename: Nuray
authors.initials: N
authors.lastname: Uslu
authors.forename: Atilla
authors.initials: A
authors.lastname: Bozkurt
authors.forename: Aysel
authors.initials: A
authors.lastname: Yuce
authors.forename: Umit
authors.initials: U
authors.lastname: Yasar
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000097:blood / Q000493:pharmacokinetics*; D000293:Adolescent; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D001711:Biotransformation; D002648:Child; D002675:Child, Preschool; D065731:Cytochrome P-450 CYP2C19; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006776:Hospitals, Pediatric; D006801:Humans; D064747:Lansoprazole; D008297:Male; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic; D054328:Proton Pump Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D014421:Turkey
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D054328:Proton Pump Inhibitors; D064747:Lansoprazole; C049963:5-hydroxymethylomeprazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; C498264:5-hydroxylansoprazole
references.citation: Eur J Clin Pharmacol. 2010 Jul;66(7):681-7
references.pmid: 20376628
references.citation: Eur J Clin Pharmacol. 2008 Oct;64(10):935-51
references.pmid: 18679668
references.citation: Curr Clin Pharmacol. 2007 Jan;2(1):93-109
references.pmid: 18690857
references.citation: Lancet. 2009 Jan 24;373(9660):309-17
references.pmid: 19108880
references.citation: Clin Pharmacol Ther. 2002 May;71(5):359-67
references.pmid: 12011821
references.citation: Br J Clin Pharmacol. 2001 Oct;52(4):349-55
references.pmid: 11678778
references.citation: Clin Pharmacol Ther. 2000 Aug;68(2):151-9
references.pmid: 10976546
references.citation: Clin Pharmacol Ther. 2009 Nov;86(5):511-8
references.pmid: 19693007
references.citation: Clin Pharmacol Ther. 2008 Feb;83(2):322-7
references.pmid: 17625515
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Feb 25;816(1-2):309-14
references.pmid: 15664363
references.citation: Pediatrics. 1999 Sep;104(3 Pt 2):640-3
references.pmid: 10469807
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2010 Sep;153B(6):1160-6
references.pmid: 20468063
references.citation: Pharmacogenomics. 2009 Jan;10(1):43-9
references.pmid: 19102714
references.citation: Eur J Clin Pharmacol. 2008 Dec;64(12):1175-9
references.pmid: 18654768
references.citation: Drug Metab Rev. 2009;41(2):89-295
references.pmid: 19514967
references.citation: Clin Pharmacol Ther. 2006 Jan;79(1):103-13
references.pmid: 16413245
references.citation: Clin Pharmacokinet. 1996 Jul;31(1):9-28
references.pmid: 8827397
references.citation: J Biol Chem. 1994 Jun 3;269(22):15419-22
references.pmid: 8195181
references.citation: Eur J Clin Pharmacol. 2009 Mar;65(3):319-20
references.pmid: 19002442
references.citation: Eur J Clin Pharmacol. 1997;53(3-4):261-4
references.pmid: 9476042
references.citation: Breast Cancer Res Treat. 2009 May;115(2):391-6
references.pmid: 18521743
references.citation: J Pharmacol Exp Ther. 2009 Apr;329(1):297-305
references.pmid: 19136640
references.citation: Pharmacogenetics. 1995 Oct;5(5):312-7
references.pmid: 8563772
references.citation: Clin Pharmacol Ther. 1998 Oct;64(4):391-401
references.pmid: 9797796
references.citation: Drug Metab Dispos. 2010 Jun;38(6):894-7
references.pmid: 20223877
references.citation: Aliment Pharmacol Ther. 2009 Aug;30(3):294-300
references.pmid: 19459830
references.citation: Br J Clin Pharmacol. 1996 Dec;42(6):771-3
references.pmid: 8971434
references.citation: Pharmacogenomics. 2008 Jun;9(6):691-702
references.pmid: 18518848
references.citation: Br J Clin Pharmacol. 2008 May;65(5):767-74
references.pmid: 18294333
references.citation: Pharmacogenetics. 2000 Apr;10(3):187-216
references.pmid: 10803676
references.citation: Pharmacogenomics J. 2011 Oct;11(5):359-67
references.pmid: 20531370
references.citation: Br J Clin Pharmacol. 2008 Mar;65(3):437-9
references.pmid: 18241287
references.citation: Eur J Clin Pharmacol. 2010 Sep;66(9):871-7
references.pmid: 20499227
references.citation: J Pharmacol Exp Ther. 1996 May;277(2):805-16
references.pmid: 8627562
references.citation: J Clin Pharmacol. 2004 Sep;44(9):966-73
references.pmid: 15317824
references.citation: Br J Clin Pharmacol. 2001 May;51(5):471-4
references.pmid: 11422005
references.citation: J Clin Pharmacol. 2004 Jun;44(6):582-9
references.pmid: 15145965
references.citation: Methods Enzymol. 1996;272:210-8
references.pmid: 8791779
references.citation: Genet Med. 2012 Jan;14(1):95-100
references.pmid: 22237437
references.citation: Drug Discov Today. 2009 Jan;14(1-2):6-15
references.pmid: 18721895