K. Park,1 J. Oh,1 J. Lee,1 S. Yoon,1 J. Cho,1 I. Jang,1 K. Lim2; 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea, Republic of, 2Department of Clinical Pharmacology and Therapeutics, CHA University School of Medicine and Bundang CHA Medical Center, Seongnam, Korea, Republic of
BACKGROUND: Human carboxylesterase 1 (CES1) is a serine esterase, which hydrolyzes various exogenous and endogenous compounds including oseltamivir, a prodrug to treat influenza. Altered CES1 gene sequences can lead to substrates’ inter-individual metabolic variability. The effect of rs200707504 (11657A>G) SNP on CES1 enzymatic activity has not been characterized yet and it was expected to decrease CES1 enzymatic activity in an in silico analysis. This study was to evaluate the effect of CES1 genetic polymorphism on the pharmacokinetics (PK) of oseltamivirin healthy volunteers.
METHODS: An open-label, single-dose PK study was conducted in 20 healthy volunteers. A single oral dose of oseltamivir 75 mg was administered to 12 subjects with wild type and 8 subjects with one 11657A>G allele. Oseltamivir and its active metabolite, oseltamivir carboxylate in plasma and urine were determined using LC-MS/MS and PK parameters were calculated by non-compartmental method. Geometric mean ratio (GMR) and 90% confidence intervals (CIs) of PK parameters (variant to wild type) were calculated.
RESULTS: Systemic exposure (AUC) to oseltamivir was increased and AUC of oseltamivir carboxylate was decreased in variant groups, but no statistical significance was observed. GMR and 90% CI of metabolic ratio (AUCinf, Oseltamivir Carboxylate/AUCinf, Oseltamivir) was 0.87 (0.66 -1.14). Amount of unchanged oseltamivir excreted in urine was also increased by 19%, but it was not statistically significant.
CONCLUSION: CES1 SNP (11657A>G) decreases systemic exposure of oseltamivir carboxylate, but the extent of decrease in AUC of active metabolite seems not to be clinically meaningful.