Ontogeny of Hepatic Drug Transporters as Quantified by LC-MS/MS Proteomics

Abstract

Protein expression of major hepatic uptake and efflux drug transporters in human pediatric (n=69) and adult (n=41) livers was quantified by LC-MS/MS. Transporter protein expression of OCT1, OATP1B3, P-gp and MRP3 was age-dependent. Particularly, significant differences were observed in transporter expression (p <0.05) between the following age-groups: neonates vs. adults (OCT1, OATP1B3, P-gp), neonates or infants vs. adolescents and/or adults (OCT1, OATP1B3 and P-gp), infants vs. children (OATP1B3 and P-gp) and adolescents vs. adults (MRP3). OCT1 showed the largest increase, of almost 5-fold, in protein expression with age. Ontogenic expression of OATP1B1 was confounded by genotype and was revealed only in livers harboring SLCO1B1*1A/*1A. In livers > 1 year, tissues harboring SLCO1B1*14/*1A showed 2.5-fold higher (P<0.05) protein expression than SLCO1B1*15/*1A. Integration of these ontogeny data in physiologically based pharmacokinetic (PBPK) models will be a crucial step in predicting hepatic drug disposition in children.