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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.

We developed a method for determining pravastatin or pitavastatin, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, in plasma using liquid chromatography and tandem mass spectrometry (LC-MS/MS). Pravastatin, pitavastatin and the internal standard fluvastatin were extracted from plasma with solid-phase extraction columns and eluted with methanol. After drying the organic layer, the residue was reconstituted in mobile phase (acetonitrile:water, 90:10, v/v) and injected onto a reversed-phase C(18) column. The isocratic mobile phase was eluted at 0.2 mL/min. The ion transitions recorded in multiple reaction monitoring mode were m/z 423 --> 101, 420 --> 290 and 410 --> 348 for pravastatin, pitavastatin and fluvastatin, respectively. The coefficient of variation of the assay precision was less than 12.4%, the accuracy exceeded 89%. The limit of detection was 1 ng/mL for all analytes. This method was used to measure the plasma concentration of pitavastatin or pravastatin from healthy subjects after a single 4 mg oral dose of pitavastatin or 40 mg oral dose of pravastatin. This is a very simple, sensitive and accurate analytic method to determine the pharmacokinetic profiles of pitavastatin or pravastatiny.

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