CYP2C19, genotypic differences

Furuta T, Shirai N, Takashima M et al. Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 2001 69[3] 158—168. 

Genotypic Differences in CYP2C19 May Modulate Disposition of Drug Therapy for H. pylori Infection and Cure Rates... 

Kita et al. [154] have undertaken a study to help predict the optimal dosage of omeprazole for extensive metabolizers in the anti-H. pylori therapy. Seven healthy Japanese subjects, classified based on the CYP2C19 genotype into extensive metabolizers (n = 4) and poor metabolizers (ft = 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 12 h after each dose of medication. After each dose was administered, the pharmacokinetic profiles of omeprazole and its two metabolites were significantly different between extensive metabolizers and poor metabolizers. The area under the plasma concentration-time curve of omeprazole in extensive metabolziers was disproportionally increased 3.2- or 19.2-fold with dose escalation from 20 to 40 to 80 mg omeprazole, respectively. In contrast, the area under the plasma concentration-time curve of omeprazole was proportionally increased with the higher dose in poor metabolizers. The area under the plasma concentration-time curve of omeprazole after 20 mg administration to poor metabolizers was almost equal to the area under the plasma concentration-time curve in extensive metabolizers after 80 mg administration. The recommended dose of omeprazole for extensive metabolizers is a maximum of 80 mg x 2/day based on pharmacokinetic considerations. 

Takahashi H, Kashima T, Nomizo Y, et al. Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes. Clin Pharmacol Ther 1998 63 519-528. 

Kawabata H, Habu Y, Tomioka H, et al. Effect of different proton pump inhibitors, differences in CYP2C19 genotype and antibiotic resistance on the eradication rate of Helicobacter pylori infection by a 1-week regimen of proton pump inhibitor, amoxicillin and clarithromycin. Aliment Pharmacol Ther 2003 17 259-264. 

Yoshiya G, Inoue Y, Kaneko S, Xateishi T., Different inhibitory effect of fluvoxamine on omeprazole metabolism between CYP2C19 genotypes, Br J Clin Pharmacol 2004 57(4) ... 

H. Hanai, K. Nakagawa et al. (2001). Effects of genotypic differences in CYP2C19 status on cure rates for Helicobacter pylori infection by dual therapy with rabeprazole plus amoxicillin. Pharmacogenetics 11, 341-348. 

Uno T, Shimizu M, Yasui-Furukori N, Sugawara K, Tateishi T. Different effects of fluvoxamine on rabeprazole pharmacokinetics in relation to CYP2C19 genotype status. BrJ Clin Pharmacol (2006) 6, 309-14. 

In a separate study in 39 healthy volunteers the interaction of the CYP2C19 genotype and the effect of three proton pump inhibitors (omeprazole 20mg/day, lansoprazole 30 mg/day, and rabeprazole 20 mg/ day for 7 days) on the antiplatelet effect of clopidogrel 75 mg were studied [63 ]. The three proton pump inhibitors affected the efficacy of clopidogrel to different... 

Furuta T, Iwaki T, Umemura K. Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes. Br J Clin Pharmacol 2010 70(3) 383-92. 

Endoscopic cure rates for esophagitis differ for poor metabolizers, heterozygotes, and extensive metabolizers. In one study, cure rates at 8 weeks were 85%, 68%, and 46%, respectively (21), and in another study were 100%, 95%, and 77%, respectively (22). In patients infected with H. pylori, the wild-type genotype for CYP2C19 is associated with a 20% lower cure rate compared to PPI plus two antibiotics in two meta-analyses of 12 and 8 studies (23,24). 

Inter-ethnicity differences observed with different CYP2C19 substrates for subjects with same genotype have been attributed to differences in substrate specificity or enzyme isoforms (Bertilsson 1992). The clearance of omeprazole is higher in Caucasian EMs than in Oriental EMs, due to an higher proportion of heterozygous EMs in this latter population (Ishizaki 1994). 

Fig. 2.5 Distribution of pharmacogenetic/pharma-cogenomic studies evaluating the impact of different genotypes of CYP2D6, CYP2C19, CYP2C9,...

---