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 lansoprazole enantiomers and contribution of cytochrome P450 enzymes to enantioselective metabolism in dogs. The mean Cmax and area under the curve (AUC) values of (+)-lansoprazole were 4-5 times greater than those of (-)-lansoprazole 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 microsomes. When the effects of ticlopidine or ketoconazole on the metabolism of lansoprazole were studied using dog liver microsomes, ticlopidine significantly inhibited the formation of 5-hydroxylansoprazole, but not another metabolite, lansoprazole sulfone; however ketoconazole significantly inhibited formation of both metabolites. When the amount of (+)- and (-)-enantiomers remaining was measured in the presence and absence of ticlopidine, the amount of (+)-lansoprazole was significantly greater than that of the (-)-lansoprazole. On the other hand, there was no significant difference between the amount of (+)- and (-)-enantiomers remaining in combination with ketoconazole. These results suggest that the enantioselective pharmacokinetics of lansoprazole enantiomers are probably ascribable to their enantioselective protein binding and/or metabolism, and among the cytochrome P450 enzymes, CYP3A contributed to the enantioselective metabolism of lansoprazole.

Effect of clarithromycin and other macrolides on the sulfoxidation and 5-hydroxylation of lansoprazole in dogs.

The purpose of this study was to evaluate a possible interaction between lansoprazole and clarithromycin as well as other macrolides in dogs. Lansoprazole (30 mg) was orally administered to male beagle dogs, with or without oral pretreatment with 200-mg clarithromycin twice a day for 5 d. The experiments had a randomized cross-over design with a two-week washout period between dosing regimens. Clarithromycin pretreatment for 5 d resulted in a significant increase in the area under the serum lansoprazole concentration-time curve (AUC), whereas the area for a lansoprazole metabolite, lansoprazole sulfone, was significantly reduced, as was the maximum serum concentration (Cmax) of lansoprazole sulfone. When the effects of clarithromycin on the metabolism of lansoprazole were studied using dog liver microsomes, it was found that clarithromycin significantly inhibited the formation of lansoprazole sulfone but not another metabolite, 5-hydroxylansoprazole. These results suggest that co-medication of lansoprazole with clarithromycin may produce a synergistic effect caused by the increased serum levels of lansoprazole of benefit in Helicobacter pylori eradication.