The novel carboxylesterase 1 variant c.662A>G may decrease the bioactivation of oseltamivir in humans

BACKGROUND Human carboxylesterase 1 (CES1) is a serine esterase that hydrolyses various exogenous and endogenous compounds including oseltamivir, a prodrug used to treat influenza. A novel CES1 c.662A>G single nucleotide polymorphism (SNP) was predicted to decrease CES1 enzymatic activity in an in silico analysis. This study evaluated the effect of the c.662A>G SNP on the pharmacokinetics (PK) of oseltamivir in humans. METHODS A single oral dose of oseltamivir at 75 mg was administered to 20 healthy subjects, 8 heterozygous c.662A>G carriers (c.662AG) and 12 non-carriers (c.662AA). The concentrations of oseltamivir and its active metabolite, oseltamivir carboxylate, were measured in plasma and urine using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK parameters were calculated using a noncompartmental method. The geometric mean ratios (GMR, c.662AG to c.662AA) of the PK parameters and their 90% confidence intervals (CI) were calculated. RESULTS The systemic exposure to oseltamivir, as assessed by the AUC0-48h of oseltamivir, was increased by 10% in c.662AG subjects, whereas the AUC0-48h of oseltamivir carboxylate was 5% lower in c.662AG subjects. The GMR and 90% CI of the metabolic ratio (AUC0-48h, Oseltamivir carboxylate/AUC0-48h, Oseltamivir) was 0.87 (0.66-1.14). The amount of unchanged oseltamivir excreted in the urine was increased by 15% in subjects with the c.662AG genotype. CONCLUSIONS This result suggests that CES1 enzymatic activity may be decreased in these heterozygous allele carriers, although further studies are warranted to investigate the clinical implications of this genetic variation on CES1 substrate drugs. TRIAL REGISTRATION ClinicalTtrials.gov NCT01902342.