title: Age-Dependent Absolute Abundance of Hepatic Carboxylesterases (CES1 and CES2) by LC-MS/MS Proteomics: Application to PBPK Modeling of Oseltamivir In Vivo Pharmacokinetics in Infants.
abstract: The age-dependent absolute protein abundance of carboxylesterase (CES) 1 and CES2 in human liver was investigated and applied to predict infant pharmacokinetics (PK) of oseltamivir. The CES absolute protein abundance was determined by liquid chromatography-tandem mass spectrometry proteomics in human liver microsomal and cytosolic fractions prepared from tissue samples obtained from 136 pediatric donors and 35 adult donors. Two surrogate peptides per protein were selected for the quantification of CES1 and CES2 protein abundance. Purified CES1 and CES2 protein standards were used as calibrators, and the heavy labeled peptides were used as the internal standards. In hepatic microsomes, CES1 and CES2 abundance (in picomoles per milligram total protein) increased approximately 5-fold (315.2 vs. 1664.4) and approximately 3-fold (59.8 vs. 174.1) from neonates to adults, respectively. CES1 protein abundance in liver cytosol also showed age-dependent maturation. Oseltamivir carboxylase activity was correlated with protein abundance in pediatric and adult liver microsomes. The protein abundance data were then used to model in vivo PK of oseltamivir in infants using pediatric physiologically based PK modeling and incorporating the protein abundance-based ontogeny function into the existing pediatric Simcyp model. The predicted pediatric area under the curve, maximal plasma concentration, and time for maximal plasma concentration values were below 2.1-fold of the clinically observed values, respectively.
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (M.B., M.V., A.M., D.K.B., B.P.); Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (M.B.); Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.); and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.).
authors.forename: Mikael
authors.initials: M
authors.lastname: Boberg
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (M.B., M.V., A.M., D.K.B., B.P.); Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (M.B.); Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.); and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.).
authors.forename: Marc
authors.initials: M
authors.lastname: Vrana
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (M.B., M.V., A.M., D.K.B., B.P.); Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (M.B.); Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.); and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.).
authors.forename: Aanchal
authors.initials: A
authors.lastname: Mehrotra
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (M.B., M.V., A.M., D.K.B., B.P.); Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (M.B.); Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.); and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.).
authors.forename: Robin E
authors.initials: RE
authors.lastname: Pearce
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (M.B., M.V., A.M., D.K.B., B.P.); Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (M.B.); Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.); and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (M.B., M.V., A.M., D.K.B., B.P.); Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (M.B.); Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.); and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.).
authors.forename: Deepak Kumar
authors.initials: DK
authors.lastname: Bhatt
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (M.B., M.V., A.M., D.K.B., B.P.); Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (M.B.); Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.); and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.).
authors.forename: J Steven
authors.initials: JS
authors.lastname: Leeder
authors.affiliation: Department of Pharmaceutics, University of Washington, Seattle, Washington (M.B., M.V., A.M., D.K.B., B.P.); Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden (M.B.); Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation, Children's Mercy Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.); and School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri (R.E.P., A.G., J.S.L.) bhagwat@uw.edu.
authors.forename: Bhagwat
authors.initials: B
authors.lastname: Prasad
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism*; D043182:Carboxylesterase / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D002853:Chromatography, Liquid; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D053139:Oseltamivir / Q000097:blood / Q000493:pharmacokinetics*; D040901:Proteomics; D053719:Tandem Mass Spectrometry
chemical_list: D053139:Oseltamivir; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; C517204:CES2 protein, human; D043182:Carboxylesterase