European Journal of Clinical Pharmacology

, Volume 61, Issue 1, pp 19–23 | Cite as

The effect of the CYP2C19 genotype on the hydroxylation index of omeprazole in South Indians

  • J Rosemary
  • C Adithan
  • N Padmaja
  • C H Shashindran
  • N Gerard
  • R Krishnamoorthy
Pharmacogenetics
First Online:
Received:
Accepted:

Abstract

To investigate the relationship between CYP2C19 genotypes and the hydroxylation index (HI) of omeprazole in the South Indian population. Healthy unrelated South Indian subjects (n=300) were separated into three groups based on their CYP2C19 genotypes. They were administered a single oral dose of 20 mg omeprazole, and venous blood was collected 3 h later. Plasma was assayed using reversed-phase high-performance liquid chromatography, and the omeprazole HI was calculated. The means of HIs in individuals with CYP2C19*1/*1 (n=124), *1/*2 (n=129) and *2/*2,*2/*3 (n=47) were 2.4, 5.3 and 22.5, respectively, and were found to be significantly different between any two groups (P<0.0001). A good correlation was established between CYP2C19 genotype and omeprazole HI (r=0.54, 95% CI 0.45–0.62; P<0.0001). Of the 300 subjects, 42 (14.0%; 95% CI 10.1–17.9) were phenotypic poor metabolizers (PMs), but only 33 of them had two mutant alleles and the remaining 9 PMs had at least one wild-type allele. Among the 258 extensive metabolizers, 14 had two mutant alleles. The prevalence of PMs in the South Indian population was 14.0%, which is similar to that in North Indians and Orientals but significantly higher than in Caucasians and Africans. A genotype–phenotype relationship was established between the CYP2C19 genotype and HI of omeprazole, but 7.7% of subjects deviated from expected genotype–phenotype associations. This could be due to an additional mutation, either in the exons/introns or in the 5′-regulatory region of the CYP2C19 gene.

Keywords

CYP2C19 Omeprazole Metabolic ratio South India 
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Notes

Acknowledgements

This research project was funded by the Indian Council of Medical Research, New Delhi, India and INSERM, Paris, France (ICMR Ref. No. 50/6/2000-BMS dated 11/12/2001). We thank Dr. Kjell Andersson, AstraZeneca, Sweden, who very kindly provided us a gift of the pure powder of 5-hydroxy omeprazole and Torrent Chemicals, Ahmedabad, India for omeprazole. We thank Mr. S. Subramaniam, Technical Officer, Division of Population Science, Modelling and Bio-informatics, Vector Control Research Centre, Pondicherry, India, for his help with statistical analysis. We are grateful to Mr. R. Balakrishnan, Mr. S. Rajan and Ms. S. Mala, for technical assistance. There are no conflicts of interest regarding financial or other relationships.

References

  1. 1.
  2. 2.
    Balian JD, Sukhova N, Harns JW, Hewett J, Pickie L, Goldstein JA et al (1995) The hydroxylation of omeprazole correlates with S-mephenytoin metabolism: a population study. Clin Pharmacol Ther 57:662–669Google Scholar
  3. 3.
    Herrlin K, Massele AY, Rimoy G, Alm C, Rais M, Ericsson O et al (2000) Slow chloroguanide metabolism in Tanzanians compared with white subjects and Asian subjects confirms a decreased CYP2C19 activity in relation to genotype. Clin Pharmacol Ther 68:189–198CrossRefGoogle Scholar
  4. 4.
    Bramness JG, Skurtveit S, Fauske L, Grung M, Molven A, Morland J et al (2003) Association between blood carisoprodol: meprobamate concentration ratios and CYP2C19 genotype in carisoprodol-drugged drivers: decreased metabolic capacity in heterozygous CYP2C19*1/CYP2C19*2 subjects? Pharmacogenetics 13:383–388CrossRefGoogle Scholar
  5. 5.
    Kosuge K, Jun Y, Watanabe H, Kimura M, Nishimoto M, Ishizaki T et al (2001) Effects of CYP3A4 inhibition by diltiazem on pharmacokinetics and dynamics of diazepam in relation to CYP2C19 genotype status. Drug Metab Dispos 29:1284–1289Google Scholar
  6. 6.
    Mamiya K, Hadama A, Yukawa E, Ieiri I, Otsubo K, Ninomiya H et al (2000) CYP2C19 polymorphism effect on phenobarbitone. Pharmacokinetics in Japanese patients with epilepsy: analysis by population pharmacokinetics. Eur J Clin Pharmacol 55(11–12):821–825CrossRefGoogle Scholar
  7. 7.
    Giancarlo GM, Venkatakrishnan K, Granda BW, von Moltke LL, Greenblatt DJ (2001) Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine. Eur J Clin Pharmacol 57:31–36CrossRefGoogle Scholar
  8. 8.
    Ward SA, Walle T, Walle UK, Wilkinson GR, Branch RA (1989) Propranolol’s metabolism is determined by both mephenytoin and debrisoquin hydroxylase activities. Clin Pharmacol Ther 45:72–79Google Scholar
  9. 9.
    de Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K, Goldstein JA (1994) Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 46:594–598PubMedGoogle Scholar
  10. 10.
    de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA (1994) The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 269:15419–15422PubMedGoogle Scholar
  11. 11.
    Xiao ZS, Goldstein JA, Hong-Guang X, Jian C, Yan F, He N et al (1997) Differences in the incidence of the CYP2C19 polymorphism affecting the S-mephenytoin phenotype in Chinese Han and Bai populations and identification of a new rare CYP2C19 mutant allele. J Pharmacol Exp Ther 281:604–609Google Scholar
  12. 12.
    Ferguson RJ, De Morais SM, Benhamou S, Bouchardy C, Blaisdell J, Ibeanu G et al (1998) Mutation of the initiation codon is responsible for poor metabolism of S-mephenytoin. J Pharmacol Exp Ther 284:356–361Google Scholar
  13. 13.
    Ibeanu GC, Blaisdell J, Ghanayem BI, Beyeler C, Benhamou S, Bouchardy C et al (1998) An additional defective allele, CYP2C19*5, contributes to the S-mephenytoin poor metabolizer phenotype in Caucasians. Pharmacogenetics 8:129–135Google Scholar
  14. 14.
    Garcia-Barcelo M, Chow LY, Kum Chiu LF, Wing YK, Shing Lee DT, Lam KL et al (1999) Frequencies of defective CYP2C19 alleles in a Hong Kong Chinese population: detection of the rare allele CYP2C19*4. Clin Chem 45:2273–2274Google Scholar
  15. 15.
    Ibeanu GC, Goldstein JA, Meyer U, Banhamou S, Bouchardy C, Dayer P et al (1998) Identification of new CYP2C19 alleles (CYP2C19*6 and CYP2C19*2B) in a Caucasian poor metabolizer of mephenytoin. J Pharmacol Exp Ther 286:1490–1495Google Scholar
  16. 16.
    Ibeanu GC, Blaisdell J, Ferguson RJ, Ghanayem BI, Brosen K, Benhamou S et al (1999) A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-mephenytoin. J Pharmacol Exp Ther 290:635–640Google Scholar
  17. 17.
    Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM et al (1997) Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American Black populations. Pharmacogenetics 7:59–64Google Scholar
  18. 18.
    Herrlin k, Massele AY, Jande M, Alm C, Tybring G, Abdi YA et al (1998) Bantu Tanzanians have a decreased capacity to metabolize omeprazole and mephenytoin in relation to their CYP2C19 genotype. Clin Pharmacol Ther 4:391–401Google Scholar
  19. 19.
    Adithan C, Gerard N, Vasu S, Rosemary J, Shashindran CH, Krishnamoorthy R (2003) Allele and genotype frequency of CYP2C19 in a Tamilian population. Br J Clin Pharmacol 56:331–333CrossRefGoogle Scholar
  20. 20.
    Lamba JK, Dhiman RK, Kohli KK (2000) CYP2C19 genetic mutations in North Indians. Clin Pharmacol Ther 68:328–335CrossRefGoogle Scholar
  21. 21.
    Yuen KY, Choy WP, Tan HY, Wong JW, Yap SP (2001) Improved high performance liquid chromatographic analysis of omeprazole in human plasma. J Pharm Biomed Anal 24:715–719CrossRefGoogle Scholar
  22. 22.
    Lamba JK, Dhiman RK, Kohli KK (1998) Genetic polymorphism of the hepatic cytochrome P450 2C19 in North Indian subjects. Clin Pharmacol Ther 63:422–427Google Scholar
  23. 23.
    Roh HK, Dahl ML, Tybring G, Yamada H, Cha YN, Bertilsson L (1996) CYP2C19 genotype and phenotype determined by omeprazole in a Korean population. Pharmacogenetics 6:547–551Google Scholar
  24. 24.
    Tassaneeyakul W, Tawalee A, Tassaneeyakul W, Kukongaviriyapan V, Blaisdell J, Goldstein JA et al (2002) Analysis of the CYP2C19 polymorphism in a North-eastern Thai population. Pharmacogenetics 12:221–225CrossRefGoogle Scholar
  25. 25.
    Gonzalez HM, Romero EM, Peregrina AA, de J Chavez T, Escobar-Islas E, Lozano F et al (2003) CYP2C19- and CYP3A4-dependent omeprazole metabolism in West Mexicans. J Clin Pharmacol 43:1211–1215CrossRefGoogle Scholar
  26. 26.
    Blaisdell J, Mohrenweiser H, Jackson J, Ferguson S, Coulter S, Chanas B et al (2002) Identification and functional characterization of new potentially defective allele of human CYP2C19. Pharmacogenetics 12:703–711CrossRefGoogle Scholar
  27. 27.
    Furuta T, Ohashi K, Kosuge K, Zhao X, Takashima M, Kimura M et al (1999) CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther 65:52–61Google Scholar
  28. 28.
    Tanigawara Y, Aoyama N, Kita T, Shirakawa K, Komada F, Kasuga M et al (1999) CYP2C19 genotype-related efficacy of omeprazole for the treatment of infection caused by Helicobacter pylori. Clin Pharmacol Ther 66:528–534Google Scholar
  29. 29.
    Kita T, Sakaeda T, Aoyama N, Sakai T, Kawahara Y, Kasuga M et al (2002) Optimal dose of omeprazole for CYP2C19 extensive metabolizers in anti-it Helicobacter pylori therapy: pharmacokinetic considerations. Biol Pharm Bull 25:923–927CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • J Rosemary
    • 1
  • C Adithan
    • 1
  • N Padmaja
    • 1
  • C H Shashindran
    • 1
  • N Gerard
    • 2
  • R Krishnamoorthy
    • 2
  1. 1.Department of Pharmacology, Pharmacogenomics LaboratoryJawaharlal Institute of Postgraduate Medical Education and Research (JIPMER)PondicherryIndia
  2. 2.INSERM U-458Hopital Robert DebreParisFrance

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