Stereoselective inhibition of cytochrome P450 forms by lansoprazole and omeprazole in vitro

다국어 초록 (Multilingual Abstract)

<P>The stereoselectivity of the inhibitory interaction potential of lansoprazole and omeprazole isomers on six human cytochrome P450 forms was evaluated using human liver microsomes. Lansoprazole enantiomers showed stereoselective inhibition of CYP2C9-catalysed tolbutamide 4-methylhydroxylation, CYP2C19-catalysed S -mephenytoin 4′-hydroxylation, CYP2D6-catalysed dextromethorphan O -demethylation, CYP2E1-catalysed chlorzoxazone 6-hydroxylation and CYP3A4-catalysed midazolam 1-hydroxylation, whereas omeprazole only inhibited CYP2C19 stereoselectively. Of the P450 forms tested, CYP2C19-catalysed S -mephenytoin 4′-hydroxylation was extensively inhibited by both the lansoprazole and omeprazole enantiomers in a competitive and stereoselective manner; the S -enantiomers of both drugs inhibited the hydroxylation more than the R -enantiomers. The estimated K i values determined for CYP2C19-catalysed S -mephenytoin 4′-hydroxylation were 0.6, 6.1, 3.4 and 5.7 µM for S -lansoprazole, R -lansoprazole, S -omeprazole and R -omeprazole, respectively. The results indicate that although both lansoprazole and omeprazole are strong inhibitors of CYP2C19, the inhibition of CYP2C19 by lansoprazole is highly stereoselective, whereas the inhibition by omeprazole is less stereoselective. In addition, S -lansoprazole, the most potent CYP2C19 inhibitor, is not a good CYP2C19-selective inhibitor owing to its inhibition of other P450 forms.</P>