title: Phenocopies of poor metabolizers of omeprazole caused by liver disease and drug treatment.
abstract: OBJECTIVE
  The kinetics of omeprazole and its primary metabolites 5'-hydroxyomeprazole and omeprazole sulfone were studied in healthy volunteers to evaluate omeprazole as a probe drug for the S-mephenytoin hydroxylase (CYP2C19) polymorphism. The plasma metabolic ratio obtained from the concentrations of omeprazole plus omeprazole sulfone over 5'-hydroxyomeprazole was investigated.
  
  
  METHODS
  The time course of the omeprazole metabolic ratio was studied in 14 extensive metabolizers, one intermediate, and five poor metabolizers of CYP2C19 after a 1-week administration of 40 mg/d omeprazole. The ratio was then determined in 187 randomly selected Caucasian hospital patients and analyzed according to liver disease and co-medication.
  
  
  RESULTS
  Between 1 and 4 h after omeprazole intake, the volunteers phenotyped by the urinary S/R-mephenytoin ratio were reliably identified as extensive metabolizers and poor metabolizers by an omeprazole metabolic ratio-antimode of 12. This antimode remained valid in eight extensive metabolizers and one poor metabolizer, who were re-investigated with 60 mg omeprazole b.i.d. for one week. Among 30 patients without concomitant drug intake, only one poor metabolizer (3.3%) was identified by both the S/R-mephenytoin ratio and omeprazole metabolic ratio. However, 30 of 47 patients with liver disease and 20 of 110 co-medicated patients without liver disease had a ratio > 12. This highly exceeded the poor metabolizer frequency of 3-4% in Caucasians.
  
  
  CONCLUSIONS
  Like other phenotypic tests, the omeprazole metabolic ratio appears to reflect CYP2C19 genotype reliably only in individuals without liver disease or co-medication. The omeprazole metabolic ratio may serve the double purpose of phenotyping for CYP2C19 and to individualize dosing in omeprazole-treated patients.
authors.affiliation: Institute of Clinical Pharmacology, Universitätsklinikum Benjamin Franklin, Berlin, Germany.
authors.forename: K L
authors.initials: KL
authors.lastname: Rost
authors.forename: J
authors.initials: J
authors.lastname: Brockmöller
authors.forename: F
authors.initials: F
authors.lastname: Esdorn
authors.forename: I
authors.initials: I
authors.lastname: Roots
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics*; D000927:Anticonvulsants / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases; D065731:Cytochrome P-450 CYP2C19; D003577:Cytochrome P-450 Enzyme System / Q000493:pharmacokinetics; D005260:Female; D005838:Genotype; D006801:Humans; D008107:Liver Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008617:Mephenytoin / Q000493:pharmacokinetics; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000493:pharmacokinetics; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D010437:Peptic Ulcer / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011110:Polymorphism, Genetic
chemical_list: D000897:Anti-Ulcer Agents; D000927:Anticonvulsants; C040450:omeprazole sulfone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D009853:Omeprazole; D008617:Mephenytoin