Inter-individual variation in the pharmacokinetics and thereby pharmacodynamics of many therapeutic agents are possibly caused by genetic polymorphisms of drug metabolizing enzymes including cytochrome P450 2C9 (CYP2C9), CYP2C19 and CYP2D6. A series of clinical studies on the CYP2C19 genotype and the pharmacokinetics and pharmacodynamics of three proton pump inhibitors (PPIs), omeprazole, lansoprazole and rabeprazole, were conducted to establish the individualized pharmacotherapy based on the CYP2C19 genotyping. [1][2][3][4][5] The subjects were classified into homo extensive metabolizers, hetero extensive metabolizers and poor metabolizers according to the CYP2C19 genotype diagnosed. The findings were summarized as follows: 1) plasma concentrations of omeprazole and lansoprazole after single oral administration were defined by the CYP2C19 genotype, whereas rabeprazole was not, 2) the CYP2C19 genotype-dependency of lansoprazole was weaker than omeprazole, and 3) hetero extensive metabolizers could be included with homo extensive metabolizers to be extensive metabolizers. There were several in vitro studies reporting that CYP2C19 and CYP3A4 were responsible for the metabolism of 3 PPIs, however, little information is available for their relative contributions on total metabolism, 6-10) that would be adequate to explain that the CYP2C19 genotypedependent pharmacokinetics was more marked for omeprazole than the other two. Herein, to validate further the difference among 3 PPIs in CYP2C19 genotype-dependency on the phenotype, a comparative in vitro study on the metabolism of 3 PPIs was conducted using human liver microsomes and newly developed anti-human CYP antibodies. MATERIALS AND METHODS MaterialsOmeprazole and its two primary metabolites, 5-hydroxyomeprazole and omeprazole sulfone, were obtained from AstraZeneca Ltd. (Osaka, Japan). Lansoprazole and its two primary metabolites, 5-hydroxylansoprazole and lansoprazole sulfone, were obtained from Takeda Pharmaceutical Co. (Osaka, Japan). The internal standard for rabeprazole (IS735), rabeprazole and its two primary metabolites, thioether rabeprazole and rabeprazole sulfone, were obtained from Eisai Co. (Tokyo, Japan). All other chemicals were of reagent grade and obtained commercially. Six lots of human liver microsomes (Table 1) were purchased from KAC Co. Ltd. (Kyoto, Japan). Anti-human CYP antibodies raised against bacterial expressed recombinant human CYP2C19 and CYP3A4 (referred to as anti-CYP2C19 and anti-CYP3A4 antibodies, respectively) were prepared in rabbits according to the method of Kaminsky et al. 11) Cross reactivity of antibodies raised against CYP2C19 and 3A4 were checked by means of ELISA. Anti-CYP2C19 antibody recognized CYP2C19 and slightly cross reacted with CYP2C9, but did not react with CYP1A2, 2D6, 2E1 and 3A4. Under the condition employed in the present study, cross reaction between CYP2C9 and anti-CYP2C19 antibody is minimized. On the other hand, anti-CYP3A4 antibody recognized CYP3A4, but did not react with CYP1A2, 2C9, 2C19, 2D6 and 2E...

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Proton pump inhibitors are occasionally used in therapy for eradicating Helicobacter pylori in the combination with antimicrobials, [1][2][3][4][5] for the prevention of gastric and duodenal ulcer diseases.1,2) Triple therapy using omeprazole, amoxicillin, and clarithromycin is now recommended for anti-H. pylori therapy because of its high eradication rate (greater than 90%), [3][4][5] although problems with this therapy have arisen including the resistance of H. pylori to clarithromycin by failure. 2,3)Omeprazole is extensively metabolized into the primary metabolites of 5Ј-hydroxyomeprazole and omeprazole sulfone (Fig. 1). Formation of the 5Ј-hydroxyomeprazole is mediated mainly by cytochrome P450 2C19 (CYP2C19) with only a minor contribution of CYP3A4 and others. 6) CYP2C19, often referred to as S-mephenytoin 4Ј-hydroxylase, shows genetically determined polymorphism of enzyme activity with bimodal distributions. 7) In 1994, two mutant alleles, CYP2C19*2 and CYP2C19*3, were found in addition to a wild-type allele, CYP2C19*1, and six different genotypic patterns were theoretically defined. [8][9][10] In our previous studies, the pharmacokinetics of omeprazole and gastric pH after omeprazole administration in healthy subjects were also defined by bimodal distribution, and two groups were genetically assigned based on CYP2C19 genotypes: extensive metabolizers and poor metabolizers. 11,12) In anti-H. pylori therapy using omeprazole (20 mgϫ2/d for 1 week), amoxicillin (500 mgϫ4/d for 1 week), and clarithromycin (200 mgϫ4/d for 1 week), patients who were poor metabolizers all achieved eradication, while 17% of extensive metabolizers failed. 13,14) Several studies have shown that this therapeutic inefficacy might be overcome by high-dose omeprazole.1) Recently, Furuta et al. 15) empirically reported that an extra-high dose of omeprazole (40 mgϫ3/d) achieved eradication in an extensive metabolizer.In the present study, a single oral dose of omeprazole 20, 40, and 80 mg was administered to 7 healthy Japanese subjects with the CYP2C19 genotype. The recommended dose of omeprazole for extensive metabolizers was estimated in anti-H. pylori therapy based on pharmacokinetic considerations. MATERIALS AND METHODS ChemicalsOmeprazole and its two metabolites, 5Ј-hydroxyomeprazole and omeprazole sulfone, were obtained In anti-Helicobacter pylori therapy using omeprazole and antimicrobials, the efficacy can be related to the CYP2C19 genotype groups; the eradication rates were 83% in extensive metabolizers and 100% in poor metabolizers. The present study was undertaken to help predict the optimal dosage of omeprazole for extensive metabolizers in this therapy. Seven healthy Japanese subjects, classified based on the CYP2C19 genotype into extensive metabolizers (n‫)4؍‬ and poor metabolizers (n‫,)3؍‬ participated in this study. Each subject received a single oral dose of omeprazole 20, 40, and 80 mg, with at least a 1-week washout period between each dose. Plasma concentrations of omeprazole and its two metabolites were monitored for...

Objective Cognitive and affective dysfunctions are important aspects for patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). Methods We herein examined the cognitive and affective ability in MS (n=35) and NMO (n=10) patients using computerized touch panel-type screening tests. Results While MS patients and normal controls (NC1, n=40) did not significantly differ in their scores from the Hasegawa dementia scale-revised (HDS-R) or the frontal assessment battery, MS patients did score significantly lower on the mini-mental state examination (MMSE). In contrast, NMO patients did not differ from the normal control group 2 (NC2, n=15) in any of the three cognitive assessments. We also examined the affective ability and found that MS patients scored significantly higher on the apathy scale (AS) compared with the NC1 group, while NMO patients scored significantly higher on the geriatric depression scale (GDS) compared with the NC2 group. Although the GDS and AS scores did not correlate with any of the cognitive assessments among MS patients, the AS scores did correlate with the MMSE and HDS-R among NMO patients. Compared with normal controls, the times to complete the flipping cards and arranging pictures games were significantly longer for MS patients but not for NMO patients. Conclusion These results indicate differences between some features of cognitive and affective dysfunctions between MS and NMO patients. Computerized touch panel-type screening tests may be a more useful and sensitive tool for the cognitive assessment of MS patients than NMO patients.

SUMMARYBackground: The polymorphic enzyme cytochrome P450 2C19 affects omeprazole metabolism. This influence on metabolism might affect serum gastrin levels, and safety, during long-term treatment of reflux oesophagitis. Aim: To examine the relationship between cytochrome P450 2C19 genotype and the safety profile of long-term omeprazole treatment. Methods: A total of 119 Japanese patients with recurrent reflux oesophagitis underwent cytochrome P450 2C19 genotyping prior to receiving daily omeprazole 10 mg or 20 mg for 6-12 months, during which adverse event frequency, serum gastrin levels and endoscopic findings were monitored.