Pharmacokinetic Differences Between Lansoprazole Enantiomers in Rats

AbstractBecause limited information is available about potential differences between the pharmacokinetics and pharmacodynamics of the enantiomers of lansoprazole, the enantioselective pharmacokinetics of the compound have been investigated in rats.There was a noticeable difference between the serum levels of the enantiomers of lansoprazole and of their metabolites, 5-hydroxylansoprazole enantiomers, after oral administration of the racemate (50 mg kg−1) to rats. Cmax (maximum serum concentration) and AUC (area under the serum concentration-time curve) for (+)-lansoprazole were 5–6 times greater than those for (—)-lansoprazole, whereas for (+)-5-hydroxylansoprazole both values were significantly smaller than those for the (—) enantiomer. CLtot/F values (where CLtot is total clearance and F is the fraction of the dose absorbed) for (+)-lansoprazole were significantly smaller than those for the (—) enantiomer. There was no significant difference between the absorption rate constants of the lansoprazole enantiomers in the in-situ absorption study. The in-vitro protein-binding study showed that binding of (+)-lansoprazole to rat serum proteins was significantly greater than for the (—) enantiomer. The in-vitro metabolic study showed that the mean metabolic ratio (45.9%) for (—)-lansoprazole was significantly greater than that (19.8%) for the (+) enantiomer in rat liver microsomes at 5.6 μM lansoprazole.These results show that the enantioselective disposition of lansoprazole could be a consequence of the enantioselectivity of plasma-protein binding and the hepatic metabolism of the enantiomers.