PMID- 16783561
OWN - NLM
STAT- MEDLINE
DCOM- 20070109
LR  - 20181211
IS  - 0031-6970 (Print)
IS  - 0031-6970 (Linking)
VI  - 62
IP  - 8
DP  - 2006 Aug
TI  - Effects of clarithromycin and verapamil on rabeprazole pharmacokinetics between 
      CYP2C19 genotypes.
PG  - 597-603
AB  - OBJECTIVE: Rabeprazole as a proton pump inhibitor (PPI) is mainly reduced to 
      rabeprazole thioether via a nonenzymatic pathway, with minor CYP2C19 and CYP3A4 
      involvement. The aim of this study was to compare possible effects of 
      clarithromycin and verapamil as inhibitors of CYP3A4 on the pharmacokinetics of 
      rabeprazole among CYP2C19 genotypes. METHODS: A three-way randomized, 
      double-blind, placebo-controlled crossover study was performed. Nineteen 
      volunteers, of whom six were homozygous extensive metabolizers (EMs), eight were 
      heterozygous EMs, and five were poor metabolizers (PMs) for CYP2C19, received 
      three 6-day courses of either daily 800 mg clarithromycin, 240 mg verapamil, or 
      placebo in a randomized fashion, with a single oral dose of 20 mg rabeprazole on 
      day 6 in all cases. Plasma concentrations of rabeprazole and rabeprazole 
      thioether were monitored up to 24 h after the dosing. RESULTS: In the control 
      phase, the AUC(0-infinity) values for rabeprazole and rabeprazole thioether were 
      1,005+/-366 and 412+/-149 ng.h/ml in homozygous EMs, 1,108+/-340 and 491+/-245 
      ng.h/ml in heterozygous EMs, and 2,697+/-364 and 2,116+/-373 ng.h/ml in PMs, 
      respectively. There were significant differences (p<0.001) in the AUC(0-infinity) 
      of rabeprazole and rabeprazole thioether among three different CYP2C19 genotypes. 
      In the clarithromycin and verapamil phases, no significant differences were found 
      in the pharmacokinetic parameters of rabeprazole compared with those in the 
      control phase irrespective of CYP2C19 genotypes, whereas the AUC(0-infinity) of 
      rabeprazole thioether was significantly increased 2.8-fold and 2.3-fold in 
      homozygous EMs (p<0.01), 2.0-fold and 2.0-fold in heterozygous EMs (p<0.05), and 
      1.6-fold and 1.9-fold in PMs (p<0.05), respectively. In each genotype group for 
      CYP2C19, there were no statistical differences in the percent increase in those 
      pharmacokinetic parameters between the clarithromycin and verapamil pretreatment 
      phases. CONCLUSION: The pharmacokinetic parameters of rabeprazole were not 
      altered by clarithromycin or verapamil irrespective of the CYP2C19 genotypes. 
      However, this result shows that both clarithromycin and verapamil significantly 
      influence the disposition of rabeprazole by inhibiting the oxidation of the 
      thioether, since the AUC(0-infinity) of rabeprazole thioether that has no effect 
      on acid secretion increased. Therefore, the pharmacokinetic interactions between 
      rabeprazole and CYP3A4 or P-glycoprotein inhibitors have limited clinical 
      significance.
FAU - Shimizu, Mikiko
AU  - Shimizu M
AD  - Department of Clinical Pharmacology, Hirosaki University School of Medicine, 
      Hirosaki 036-8562, Japan.
FAU - Uno, Tsukasa
AU  - Uno T
FAU - Yasui-Furukori, Norio
AU  - Yasui-Furukori N
FAU - Sugawara, Kazunobu
AU  - Sugawara K
FAU - Tateishi, Tomonori
AU  - Tateishi T
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20060617
PL  - Germany
TA  - Eur J Clin Pharmacol
JT  - European journal of clinical pharmacology
JID - 1256165
RN  - 0 (2-Pyridinylmethylsulfinylbenzimidazoles)
RN  - 0 (Cytochrome P-450 Enzyme Inhibitors)
RN  - 0 (Enzyme Inhibitors)
RN  - 32828355LL (Rabeprazole)
RN  - CJ0O37KU29 (Verapamil)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases)
RN  - EC 1.14.14.1 (CYP2C19 protein, human)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP2C19)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.14.14.55 (CYP3A4 protein, human)
RN  - H1250JIK0A (Clarithromycin)
SB  - IM
MH  - 2-Pyridinylmethylsulfinylbenzimidazoles/blood/metabolism/*pharmacokinetics
MH  - Area Under Curve
MH  - Aryl Hydrocarbon Hydroxylases/drug effects/*genetics
MH  - Clarithromycin/*pharmacology
MH  - Cytochrome P-450 CYP2C19
MH  - Cytochrome P-450 CYP3A
MH  - Cytochrome P-450 Enzyme Inhibitors
MH  - Double-Blind Method
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - Genotype
MH  - Half-Life
MH  - Humans
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Middle Aged
MH  - Mixed Function Oxygenases/drug effects/*genetics
MH  - Rabeprazole
MH  - Verapamil/*pharmacology
EDAT- 2006/06/20 09:00
MHDA- 2007/01/11 09:00
CRDT- 2006/06/20 09:00
PHST- 2006/03/19 00:00 [received]
PHST- 2006/05/02 00:00 [accepted]
PHST- 2006/06/20 09:00 [pubmed]
PHST- 2007/01/11 09:00 [medline]
PHST- 2006/06/20 09:00 [entrez]
AID - 10.1007/s00228-006-0152-9 [doi]
PST - ppublish
SO  - Eur J Clin Pharmacol. 2006 Aug;62(8):597-603. doi: 10.1007/s00228-006-0152-9. 
      Epub 2006 Jun 17.