title: Carboxylesterase 1 polymorphism impairs oseltamivir bioactivation in humans.
abstract: Bioactivation of the antiviral agent oseltamivir to active oseltamivir carboxylate is catalyzed by carboxylesterase 1 (CES1). After the screening of 860 healthy Finnish volunteers for the CES1 c.428G>A (p.Gly143Glu, rs121912777) polymorphism, a pharmacokinetic study with 75 mg oseltamivir was carried out in c.428G>A carriers and noncarriers. Heterozygous c.428GA carriers (n = 9) had 18% larger values of oseltamivir area under the plasma concentration-time curve from 0 h to infinity (AUC(0-∞)) (P = 0.025) and 23% smaller carboxylate-to-oseltamivir AUC(0-∞) ratio (P = 0.006) than noncarriers (n = 12). This shows that the CES1 c.428G>A polymorphism impairs oseltamivir bioactivation in humans.
authors.affiliation: Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: E K
authors.initials: EK
authors.lastname: Tarkiainen
authors.forename: J T
authors.initials: JT
authors.lastname: Backman
authors.forename: M
authors.initials: M
authors.lastname: Neuvonen
authors.forename: P J
authors.initials: PJ
authors.lastname: Neuvonen
authors.forename: M
authors.initials: M
authors.lastname: Schwab
authors.forename: M
authors.initials: M
authors.lastname: Niemi
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D005838:Genotype; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D009981:Influenza B virus / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy*; D008297:Male; D053139:Oseltamivir / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D011110:Polymorphism, Genetic; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D053139:Oseltamivir; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; C535162:oseltamivir carboxylate