Pharmacokinetic differences between pantoprazole enantiomers in rats.

PURPOSE

The purpose of this study was to quantitatively clarify the contribution of the absorption, protein binding, and metabolism of cytochrome P450 enzymes to the enantioselective pharmacokinetics of pantoprazole enantiomers in rats.

METHODS

The enantioselective pharmacokinetics of pantoprazole enantiomers was estimated by an oral administration of racemic pantoprazole to rats. The pharmacokinetic differences between pantoprazole enantiomers were evaluated by the experiments of the in situ perfusion into rat small intestine, the protein binding, and the in vitro metabolism in rat liver microsomes of pantoprazole enantiomers.

RESULTS

The mean area under the curve value of S-pantoprazole was 1.5 times greater than that of R-pantoprazole after administration of racemic pantoprazole to rats (20 mg/kg, p.o.). There were significant differences in k(e) (p < 0.05), t1/2 (p < 0.01), and mean residence time (p < 0.01) values between the two enantiomers. In the in situ absorption study, the absorption rate constants were of no significant differences between the two enantiomers. The mean unbound fraction of R-pantoprazole was slightly greater than that of S-pantoprazole. The intrinsic clearance (CLint) of the formation of the 5'-O-demethyl metabolite from S-pantoprazole was 4-fold lower than that from R-pantoprazole. However, the CLint value for the sulfone and 6-hydroxy metabolites from S-pantoprazole was higher than that from R-pantoprazole. The sum of the CLint of the formation of all three metabolites was 3.06 and 4.82 mL/min/mg protein for S- and R-pantoprazole, respectively.

CONCLUSIONS

This study suggests that the enantioselective pharmacokinetics of pantoprazole enantiomers in rats is probably ascribable to their enantioselective metabolism, which is contributed by all the three metabolic pathways, including sulfoxide oxidation, 4'-O-demethylation, and 6-hydroxylation.