title: Association of Oseltamivir Activation with Gender and Carboxylesterase 1 Genetic Polymorphisms.
abstract: Oseltamivir, an inactive anti-influenza virus prodrug, is activated (hydrolysed) in vivo by carboxylesterase 1 (CES1) to its active metabolite oseltamivir carboxylate. CES1 functions are significantly associated with certain CES1 genetic variants and some non-genetic factors. The purpose of this study was to investigate the effect of gender and several CES1 genetic polymorphisms on oseltamivir activation using a large set of individual human liver samples. CES1-mediated oseltamivir hydrolysis and CES1 genotypes, including the G143E (rs71647871), rs2244613, rs8192935, the -816A>C (rs3785161) and the CES1P1/CES1P1VAR, were determined in 104 individual human livers. The results showed that hepatic CES1 protein expression in females was 17.3% higher than that in males (p = 0.039), while oseltamivir activation rate in the livers from female donors was 27.8% higher than that from males (p = 0.076). As for CES1 genetic polymorphisms, neither CES1 protein expression nor CES1 activity on oseltamivir activation was significantly associated with the rs2244613, rs8192935, -816A>C or CES1P1/CES1P1VAR genotypes. However, oseltamivir hydrolysis in the livers with the genotype 143G/E was approximately 40% of that with the 143G/G genotype (0.7 ± 0.2 versus 1.8 ± 1.1 nmole/mg protein/min, p = 0.005). In summary, the results suggest that hepatic oseltamivir activation appears to be more efficient in females than that in males, and the activation can be impaired by functional CES1 variants, such as the G143E. However, clinical implication of CES1 gender differences and pharmacogenetics in oseltamivir pharmacotherapy warrants further investigations.
authors.affiliation: Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Xinwen
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Pharmacy, University of Connecticut, Storrs, CT, USA.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Eyler
authors.affiliation: Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA.|The Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA.|The Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Mueller
authors.affiliation: Department of Clinical Pharmacy, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Hao-Jie
authors.initials: HJ
authors.lastname: Zhu
mesh_terms: D065767:Activation, Metabolic; D000483:Alleles; D000998:Antiviral Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D056726:Genetic Association Studies; D006801:Humans; D006868:Hydrolysis; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D053139:Oseltamivir / Q000378:metabolism / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide; D011355:Prodrugs / Q000378:metabolism / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D012727:Sex Characteristics; D014015:Tissue Banks
chemical_list: D000998:Antiviral Agents; D015415:Biomarkers; D011355:Prodrugs; D053139:Oseltamivir; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human