Stereoselective metabolism of lansoprazole by human liver cytochrome P450 enzymes.
The stereoselective metabolism of lansoprazole enantiomers was evaluated by incubation of human liver microsomes and cDNA-expressed cytochrome p450 (p450) enzymes to understand and predict their stereoselective disposition in humans in vivo. The intrinsic clearances (Clint) of the formation of both hydroxy and sulfone metabolites from S-lansoprazole were 4.9- and 2.4-fold higher than those from the R-form, respectively. The sums of formation Clint of both metabolites were 13.5 and 57.3 microl/min/mg protein for R- and S-lansoprazole, respectively, suggesting that S-lansoprazole would be cleared more rapidly than the R-form. The p450 isoform selective inhibition study in liver microsomes, and the incubation study of cDNA-expressed enzymes, demonstrated that the stereoselective sulfoxidation is mediated by CYP3A4 and that the hydroxylation is mediated by CYP2C9 and CYP3A4 as well as by CYP2C19. Total Clint values of hydroxy and sulfone metabolite formation catalyzed by all these p450 enzymes were consistently higher for S-lansoprazole than for the R-form. The CYP3A4 produced the greatest difference of Clint between S- and R-enantiomers, mainly due to a difference of sulfoxidation metabolism (Clint 76.5 versus 10.8 microl/min/nmol of p450, respectively), whereas CYP2C19-catalyzed hydroxylation resulted in a minor difference of Clint between S- and R-enantiomers (179.6 versus 143.3 microl/min/nmol of p450, respectively). However, the affinity of CYP2C19 on hydroxylation was 5.7-fold higher for S-enantiomer than for the R-form (Km 2.3 versus 13.1 microM), suggesting that the role of CYP2C19 on stereoselective hydroxylation would be more prominent at concentrations around the usual therapeutic level. These findings suggest that both CYP2C19 and CYP3A4 are major enzymes contributing to the stereoselective disposition of lansoprazole, but stereoselective hydroxylation of lansoprazole enantiomers is mainly influenced by CYP2C19, especially at the usual therapeutic doses.
Kim
Kyoung-Ah
KA
Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine Clinical Pharmacology Center, Busan Paik Hospital Busan, Korea.
Kim
Min-Jung
MJ
Park
Ji-Young
JY
Shon
Ji-Hong
JH
Yoon
Young-Ran
YR
Lee
Sang-Seop
SS
Liu
Kwang-Hyeon
KH
Chun
Jin-Ho
JH
Hyun
Myung-Ho
MH
Shin
Jae-Gook
JG
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D064747:Lansoprazole; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism*; D013237:Stereoisomerism
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D064747:Lansoprazole; D003577:Cytochrome P-450 Enzyme System; D009853:Omeprazole