Ilaprazole, a new proton pump inhibitor, is primarily metabolized to ilaprazole sulfone by CYP3A4 and 3A5.
Ilaprazole is a new proton pump inhibitor, designed for treatment of gastric ulcers, and developed by Il-Yang Pharmaceutical Co (Seoul, Korea). It is extensively metabolised to the major metabolite ilaprazole sulfone.        In the present study, several in vitro approaches were used to identify the cytochrome P450 (CYP) enzymes responsible for ilaprazole sulfone formation. Concentrations of ilaprazole sulfone were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).        Incubation of ilaprazole with cDNA-expressed recombinant CYPs indicated that CYP3A was the major enzyme that catalyses ilaprozole to ilaprazole sulfone. This reaction was inhibited significantly by ketoconazole, a CYP3A inhibitor, and azamulin, a mechanism-based inhibitor of CYP3A, while no substantial effect was observed using selective inhibitors for eight other P450s (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1).        In addition, the formation of ilaprazole sulfone correlated well with CYP3A-catalysed testosterone 6β-hydroxylation and midazolam 1'-hydroxylation in 20 different human liver microsome panels. The intrinsic clearance of the formation of ilaprazole sulfone by CYP3A4 was 16-fold higher than that by CYP3A5.        Collectively, these results indicate that the formation of the major metabolite of ilaprazole, ilaprazole sulfone, is predominantly catalysed by CYP3A4/5.
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan, Korea.
Kyung-Ah
KA
Seo
So-Jeong
SJ
Lee
Kwon-Bok
KB
Kim
Soo Kyung
SK
Bae
Kwang-Hyeon
KH
Liu
Dong-Hyun
DH
Kim
Jae-Gook
JG
Shin
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D054328:Proton Pump Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013450:Sulfones / Q000737:chemistry / Q000378:metabolism*; D013454:Sulfoxides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D001562:Benzimidazoles; D007527:Isoenzymes; D054328:Proton Pump Inhibitors; D011994:Recombinant Proteins; D013450:Sulfones; D013454:Sulfoxides; C574790:ilaprazole sulfone; C119615:ilaprazole; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human