title: Identification of the time-point which gives a plasma rabeprazole concentration that adequately reflects the area under the concentration-time curve.
abstract: OBJECTIVE
  The purpose of this study is to evaluate whether a simple formula using limited blood samples can predict the area under the plasma rabeprazole concentration-time curve (AUC) in co-administration with CYP inhibitors.
  
  
  METHODS
  A randomized double-blind placebo-controlled crossover study design in three phases was conducted at intervals of 2 weeks. Twenty-one healthy Japanese volunteers, including three CYP2C19 genotype groups, took a single oral 20-mg dose of rabeprazole after three 6-day pretreatments, i.e., clarithromycin 800 mg/day, fluvoxamine 50 mg/day, and placebo. Prediction formulas of the AUC were derived from pharmacokinetics data of 21 subjects in three phases using multiple linear regression analysis. Ten blood samples were collected over 24 h to calculate AUC. Plasma concentrations of rabeprazole was measured by an HPLC-assay (l.l.q.=1 ng/ml).
  
  
  RESULTS
  The AUC was based on all the data sets (n=63). The linear regression using two points (C3 and C6) could predict AUC(0-infinity) precisely, irrespective of CYP2C19 genotypes and CYP inhibitors (AUC(0-infinity)=1.39xC3+7.17xC6+344.14, r (2)=0.825, p<0.001).
  
  
  CONCLUSIONS
  The present study demonstrated that the AUC of rabeprazole can be estimated by the simple formula using two-point concentrations. This formula can be more accurate for the prediction of AUC estimation than that reflected by CYP2C19 genotypes without any determination, even if there are significant differences for the CYP2C19 genotypes. Therefore, this prediction formula might be useful to evaluate whether CYP2C19 genotypes really reflects the curative effect of rabeprazole.
authors.affiliation: Department of Pharmacy, Hirosaki University Hospital, Hirosaki, Japan.
authors.forename: Takenori
authors.initials: T
authors.lastname: Niioka
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Uno
authors.forename: Norio
authors.initials: N
authors.lastname: Yasui-Furukori
authors.forename: Mikiko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Kazunobu
authors.initials: K
authors.lastname: Sugawara
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tateishi
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000328:Adult; D000465:Algorithms; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D017291:Clarithromycin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D016666:Fluvoxamine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006207:Half-Life; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D064750:Rabeprazole; D012044:Regression Analysis; D013440:Sulfides / Q000097:blood / Q000378:metabolism; D013997:Time Factors
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D013440:Sulfides; C523099:rabeprazole-thioether; D064750:Rabeprazole; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017291:Clarithromycin; D016666:Fluvoxamine