Aim: CYP2C9 enzyme metabolizes numerous clinically important drugs. The aim of this study is to investigate the frequencies of CYP2C9 genotypes and the effects of selected alleles on losartan pharmacokinetics in a large sample of the Korean population. Methods: The CYP2C9 gene was genotyped in 1796 healthy Korean subjects. CYP2C9 alleles (CYP2C9*1, *2, *3, and *13 alleles) were measured using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and direct sequencing assay. The enzymatic activity of each CYP2C9 genotype was evaluated using losartan as the substrate. Results: The frequencies of CYP2C9*1, *3, and *13 allele were 0.952 (95% confidence interval 0.945-0.959), 0.044 (95% CI 0.037-0.051), and 0.005 (95% CI 0.003-0.007), respectively. The frequencies of the CYP2C9*1/*1, *1/*3, *1/*13, and *3/*3 genotypes were 0.904 (95% CI 0.890-0.918), 0.085 (95% CI 0.072-0.098), 0.009 (95% CI 0.005-0.013), and 0.001 (95% CI 0.000-0.002), respectively. In the pharmacokinetics studies, the AUC 0-∞ of losartan in CYP2C9*3/*3 subject was 1.42-fold larger than that in CYP2C9*1/*1 subjects, and the AUC 0-∞ of E-3174, a more active metabolite of losartan, in CYP2C9*3/*3 subject was only 12% of that in CYP2C9*1/*1 subjects. Conclusion:The results confirmed the frequencies of CYP2C9 genotypes in a large cohort of Koreans, and detected the CYP2C9*3/*3 genotype. CYP2C9*3/*3 subjects metabolized much less losartan into E-3174 than CYP2C9*1/*1 subjects.

No abstract

Introduction: Acute myocarditis is extremely heterogenous in causal agents, clinical courses, and geographic regions. There is little long-term outcomes data for acute myocarditis prior to the COVID-19 pandemic. Hypothesis: The clinical profile of acute myocarditis would differ according to age at presentation. Methods: A retrospective nationwide cohort study was performed. All patients aged 20-79 who were hospitalized for acute myocarditis without underlying cardiac diseases from 2006 to 2018 in Korea. Complicated phenotype was defined as requiring hemodynamic or major organ support. Over 10 years, all-cause mortality and acute myocarditis-driven excess mortality were evaluated according to young-adult (20-39 years), mid-life (40-59 years), and older-adult (60-79 years) age groups. Results: Among 2988 patients (mean age 51.0 years), 362 (12.1%) were of complicated phenotype. All-cause death at 30 days occurred in 40 (4.7%), 52 (4.8%), and 105 (10.0%) patients in the young-adult, mid-life, and older adult groups, respectively (Figure A). Most short-term deaths occurred within 37 days of admission, primarily in the complicated phenotype. However, higher excess mortality compared to the age- and sex-matched general population remained over the 10-year follow-up even in younger patients with non-complicated phenotypes (Figure B). Conclusions: In patients with de novo acute hospitalized myocarditis, short-term mortality is high both in young and older adults, particularly those with advanced age, non-cardiac comorbidities, and severe clinical presentation. Furthermore, long-term excess mortality remains high over 10 years after index hospitalization. A cardiac monitoring strategy should be discussed for post-myocarditis patients against the long-term risk.