Various PPIs as inhibitors of diazepam N-demethylation in the presence of human primary hepatocytes coincubated with human serum
| PPI (Final Concentration)a | % Inhibitionb | % Inhibitionin vivo (90% CI)c | |
|---|---|---|---|
| Hepatocyte Preparation 1 (n = 1 Organ Donor) | Hepatocyte Preparation 2 (Pool of n = 20 Organ Donors) | ||
| Omeprazole (2.5 μM) | 30.2 ± 5.4 | 23.2 ± 5.2 | 38 (28, 49)d, 46 (28, 61)e |
| Esomeprazole (18.7 μM) | 60.1 ± 1.4 | 23.6 ± 4.4 | 79 (52, 99) |
| Lansoprazole (2.9 μM) | <2 | <2 | 19 (<1, 33) |
| Dexlansoprazole (2.9 μM) | 8.0 ± 3.8 | <2 | 10 (2, 19) |
| Pantoprazole (6.7 μM) | <2 | 4.9 ± 2.8 | <1 (<1, 20) |
| Rabeprazole (1.4 μM) | 13.5 ± 6.4 | 2.8 ± 2.9 | <1 (<1, 3) |
↵a Each PPI was added at a single concentration, based on its estimated Cmax,portal (see Materials and Methods). For dexlansoprazole, it was assumed that its Cmax,portal is identical to that of lansoprazole; assumed an oral dose of 20, 30, 30, 40, and 40 mg for omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole, respectively.
↵b Data are reported as percentage of inhibition, relative to a DMSO alone control, and represent mean ± S.D. of triplicate determinations. In the presence of DMSO alone, the rate of N-desmethyl-diazepam formation was 28 ± 0.4 pmol/min per 106 cells (hepatocyte preparation 1) and 15 ± 0.7 pmol/min per 106 cells (hepatocyte preparation 2). The final diazepam concentration was 1 μM (preparation 1) and 2 μM (preparation 2); close to the estimated Cmax,portal for diazepam (data not shown). Hepatocyte preparation 1 exhibited higher CYP2C19 activity [(S)-mephenytoin 4′-hydroxylase = 95 pmol/min per 106 cells vs. 15 pmol/min per 106 cells].
↵c Percentage of inhibitionin vivo was calculated based on the reported effect of each PPI on the AUC of diazepam (see Materials and Methods, eqs. 17 and 18).
↵d Percentage of inhibitionin vivo was calculated based on the AUCi/AUCc ratio reported by Ishizaki et al. (1995).
↵e Percentage of inhibitionin vivo was calculated based on the AUCi/AUCc ratio reported by Andersson et al. (1990).