Abstract
The age-dependent absolute protein abundance of carboxylesterase 1 and 2 (CES1 and CES2) in human liver was investigated and applied to predict infant pharmacokinetics (PK) of oseltamivir. The CES absolute protein abundance was determined by LC-MS/MS proteomics in human liver microsomal and cytosolic fractions prepared from tissue samples obtained from 136 pediatric 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 (pmol/mg total protein) increased ~5 fold (315.2 vs. 1664.4 pmol) and ~3-fold (59.8 vs. 174.1 pmol) from neonates to adults, respectively. CES1 protein abundance in liver cytosol also showed age-dependent maturation. Oseltamivir carboxylase activity was correlated with protein expression 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 pharmacokinetic (pPBPK) modeling and incorporating the protein abundance-based ontogeny function into the existing pediatric Simcyp model. The predicted pediatric AUC, Cmax and Tmax were below 2.1-fold of the clinically observed values, respectively.
- carboxylesterases
- mass spectrometry/MS
- modeling and simulation
- pharmacokinetics
- physiologically-based pharmacokinetic modeling/PBPK
- prodrugs
- proteomics
- The American Society for Pharmacology and Experimental Therapeutics