title: Rapid and ultra-rapid metabolizers with CYP2C19*17 polymorphism do not respond to standard therapy with proton pump inhibitors.
abstract: OBJECTIVE
  Polymorphisms in genes encoding drug metabolizing enzymes may lead to varied enzyme activity and inter-individual variability in drug efficacy and/or toxicity. Since CYP2C19 and CYP3A4 genes code for enzymes involved in metabolizing wide variety of drugs including proton pump inhibitors, we sought to identify polymorphisms in these genes in order to study their impact on drug metabolism in subjects.
  
  
  METHODS
  DNA was isolated from healthy individuals including tribals and genotyped for 11 single nucleotide polymorphisms in CYP2C19 and 6 polymorphisms in CYP3A4. Individuals were categorized into different phenotypes based on their drug metabolizing genotype. Volunteers from each group were administered proton pump inhibitors (Esomeprazole, Pantoprazole; 40 mg/day) for 5 days followed by pharmacokinetic studies and measurement of intra-gastric pH.
  
  
  RESULTS
  Of the 17 polymorphisms studied, only CYP2C19*2,*3,*17 and CYP3A4*1B polymorphisms were observed. In comparison to urban individuals, a significantly (p = 0.0003) higher number of poor metabolizers were noted in the tribal individuals. Pantoprazole was found to be most effective in poor metabolizers in terms of area under the curve and Tmax. No significant difference was observed in the intra-gastric pH at baseline and day 6 in rapid and ultra-rapid metabolizers.
  
  
  CONCLUSIONS
  Our study has demonstrated that 19.7% of our subjects are carriers of the CYP2C19*17 allele who did not respond to the standard dose of proton pump inhibitors. Genetic screening to identify subjects with variant alleles would thus be useful for personalization of therapy with proton pump inhibitors.
authors.affiliation: Asian Healthcare Foundation, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Deshpande
authors.affiliation: Asian Healthcare Foundation, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India.
authors.forename: Sharanya
authors.initials: S
authors.lastname: V
authors.affiliation: Asian Healthcare Foundation, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India.
authors.forename: Ravi Kanth
authors.initials: RK
authors.lastname: V V
authors.affiliation: Asian Healthcare Foundation, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India.
authors.forename: Murthy
authors.initials: M
authors.lastname: H V V
authors.affiliation: Asian Healthcare Foundation, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India.
authors.forename: Sasikala
authors.initials: S
authors.lastname: M
authors.affiliation: Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India.
authors.forename: Rupa
authors.initials: R
authors.lastname: Banerjee
authors.affiliation: Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India.
authors.forename: Manu
authors.initials: M
authors.lastname: Tandan
authors.affiliation: Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India.
authors.forename: Nageshwar Reddy
authors.initials: NR
authors.lastname: D
keywords: Drug metabolizing enzymes; Genotyping; Intragastric pH; Pharmacogenomics