Pharmacokinetic differences between lansoprazole enantiomers and contribution of cytochrome P450 isoforms to enantioselective metabolism of lansoprazole in dogs

The purpose of this study was to evaluate the pharmacokinetics of lansopraz ole enantiomers and contribution of cytochrome P450 enzymes to enantioselec tive metabolism in dogs. The mean C-max and area under the curve (AUC) valu es of (+)-lansoprazole were 4-5 times greater than those of (-)-lansoprazol e following oral administration of 30-mg racemic lansoprazole to dogs. The CLtot/F values of (+)-lansoprazole were significantly smaller than those of (-)-lansoprazole (p < 0,05), The mean unbound fraction of (-)-lansoprazole was significantly greater than that of the (+)-lansoprazole. The amount of (+)-lansoprazole remaining was significantly greater than that of the (-)- lansoprazole after incubation of racemic lansoprazole in dog liver microsom es. When the effects of ticlopidine or ketoconazole on the metabolism of la nsoprazole were studied using dog liver microsomes, ticlopidine significant ly inhibited the formation of 5-hydroxylansoprazole, but not another metabo lite, lansoprazole sulfone: however ketoconazole significantly inhibited fo rmation of both metabolites, When the amount of (+)- and (-)-enantiomers re maining was measured in the presence and absence of ticlopidine, the amount of (+)-lansoprazole was significantly greater than that of the (-)-lansopr azole. On the other hand, there was no significant difference between the a mount of (+)- and (-)-enantiomers remaining in combination with ketoconazol e. These results suggest that the enantioselective pharmacokinetics of lans oprazole enantiomers are probably ascribable to their enantioselective prot ein binding and/or metabolism, and among the cytochrome P450 enzymes, CYP3A contributed to the enantioselective metabolism of lansoprazole.