Time-dependent amplified pharmacokinetic and pharmacodynamic response of rabeprazole in CYP2C19 poor metabolizers and its clinical significance in the treatment of Helicobacter pylori.

Introduction: Rabeprazole was shown to have a more rapid onset of action and greater antisecretory activity than other PPIs. Some investigators have suggested that a 4-day triple therapy involving rabeprazole achieves a comparable eradication rate of 90% with a 7-day triple therapy regimen. The cure rate of H. pylori is shown to be higher in CYP2C19 poor metabolizers (PMs) than in CYP2C19 extensive metabolizers (EMs). However, the metabolism of rabeprazole is usually considered to be less dependent of CYP2C19 genotypes. The aim of this study was to investigate the possible scenario for the effects of rabeprazole in the short-term treatment of H. pylori infection. Methods: Twenty mg of rabeprazole was given twice daily for 3 consecutive days then once daily at the fourth day to twelve healthy volunteers identified as CYP2C19 PMs or EMs. On day-1, aliquots of 10-ml blood samples were drawn 30 minutes before drug administration and 0.5, 1,2,3,4,5,6,7,8,10 and 12 hours after the starx of dosing. On day-4, blood samples were obtained as those in the first day except one additional 24-hour sample. Both pharmacokinetic (PK) and pharmacodynamic (PD) parameters were compared between different CYP2C19 genotype groups. Results: The plasma levels of both rabeprazole and rabeprazole thioether were much higher in CYP2CI9 PMs than in EMs, while there is no difference between day-1 and day-4 of dosing within the same genotype groups. In addition, only CYP2C19 PMs exhibit significant higher plasma gastrin levels on the fourth day compared to those on the first day. The PK/PD relationship of rabeprazole appears to be time-dependent. Conclusions: In terms of antisecretory and bacteriostatic effects, the PK/PD data suggest that CYP2C19 PMs might be subject to advantageous conditions for the treatment of H. pylori infection using rabeprazole, which might also provide rationale for the regimen design. [ABSTRACT FROM AUTHOR]