INTERPHENOTYPE DIFFERENCES IN DISPOSITION AND EFFECT ON GASTRIN-LEVELS OF OMEPRAZOLE - SUITABILITY OF OMEPRAZOLE AS A PROBE FOR CYP2C19

1 Fourteen healthy Swedish Caucasian subjects were given 20 mg of omep razole orally each morning for 8 days. The subjects included five poor metabolisers (PM) of S-mephenytoin, four heterozygous extensive metab olisers (hetEM) and five subjects with a very rapid metabolism (rapidE M). 2 After the first dose, the relative mean areas under the plasma c oncentration vs time curve (AUG) of omeprazole in rapidEM, hetEM and P M were 1:3.7:20 (all different, P < 0.001). A similar relation was see n in the AUC(0,10 h) of the sulphone metabolite (1:3:12). Concentratio ns of hydroxyomeprazole were higher in EM than in PM confirming that t he hydroxy, but not the sulphone metabolite, is formed by the S-mephen ytoin hydroxylase (CYP2C19). After 8 days of treatment, the difference s between groups were similar. 3 After both the first and the eighth d oses, the omeprazole/hydroxyomeprazole plasma concentration ratio, det ermined 3 h after drug intake, correlated with the mephenytoin S/R rat io (r(s) = 0.94; P < 0.001; n = 14) suggesting that omeprazole might b e used to phenotype for CYP2C19. 4 After the first dose of omeprazole, there was no difference in the AUC(0,10 h) of plasma gastrin between the three groups. From the first to the eighth dose, the AUC(0,10) of gastrin increased significantly in both hetEM and PM, while there was no change in the rapidEM. After the eighth dose, the AUC(0,10) of gast rin correlated significantly with the AUC of omeprazole in plasma (r(s ) = 0.79; P < 0.01; n = 13).