title: Comparison of an increased dosage regimen of rabeprazole versus a concomitant dosage regimen of famotidine with rabeprazole for nocturnal gastric acid inhibition in relation to cytochrome P450 2C19 genotypes.
abstract: OBJECTIVE
  A concomitant dosage regimen of a histamine 2 receptor antagonist with a proton pump inhibitor (PPI) effectively decreases the incidence of nocturnal acid breakthrough, which is one of the problems encountered when acid-related diseases are treated with a PPI alone. We compared the effectiveness of an increased dosage regimen of rabeprazole with that of a concomitant dosage regimen of rabeprazole with famotidine, relative to cytochrome P450 (CYP) 2C19 genotype status, on nocturnal acid inhibition.
  
  
  METHODS
  Fifteen Helicobacter pylori-negative volunteers, consisting of 5 homozygous extensive metabolizers (EMs), 6 heterozygous EMs, and 4 poor metabolizers (PMs) of CYP2C19, took 20 mg rabeprazole, 40 mg rabeprazole, and 20 mg rabeprazole plus 20 mg famotidine at bedtime (at 10 PM) for 8 days. The subjects then underwent 24-hour intragastric pH monitoring on day 8.
  
  
  RESULTS
  For the 20-mg rabeprazole, 40-mg rabeprazole, and concomitant dosage regimens, the median percent times and ranges when nocturnal intragastric pH values were lower than 4.0 were 78.8% (47.5%-98.0%), 45.3% (29.0%-52.2%), and 15.5% (0.0%-40.8%), respectively, for homozygous EMs; 51.0% (7.0%-91.6%), 41.3% (33.0%-59.0%), and 18.5% (8.4%-31.9%), respectively, for heterozygous EMs; and 4.5% (2.0%-31.2%), 9.5% (0.0%-31.1%), and 9.3% (0.0%-14.7%), respectively, for PMs. Although significant differences in acid inhibition between the different CYP2C19 genotypes were observed when rabeprazole alone was given (P = .016 for 20 mg rabeprazole and P = .023 for 40 mg rabeprazole), such differences were not observed when famotidine was concomitantly given (P = .206).
  
  
  CONCLUSIONS
  The combination regimen of famotidine plus rabeprazole is more effective for nocturnal acid inhibition in homozygous and heterozygous EMs than the increased dosage regimen of rabeprazole. This concomitant therapy could be a rescue regimen for patients with nocturnal acid breakthrough refractory to a standard PPI therapy who are likely to be CYP2C19 EMs.
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan. mitsu@hama-med.ac.jp
authors.forename: Mitsushige
authors.initials: M
authors.lastname: Sugimoto
authors.forename: Takahisa
authors.initials: T
authors.lastname: Furuta
authors.forename: Naohito
authors.initials: N
authors.lastname: Shirai
authors.forename: Akiko
authors.initials: A
authors.lastname: Nakamura
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kajimura
authors.forename: Akira
authors.initials: A
authors.lastname: Hishida
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Ohashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishizaki
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D002940:Circadian Rhythm; D065731:Cytochrome P-450 CYP2C19; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015738:Famotidine / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005838:Genotype; D006635:Histamine H2 Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics; D009853:Omeprazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011110:Polymorphism, Genetic; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors; D064750:Rabeprazole
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D006635:Histamine H2 Antagonists; D064750:Rabeprazole; D015738:Famotidine; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D000251:Adenosine Triphosphatases; D006180:Proton-Translocating ATPases; D009853:Omeprazole