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

• Published in: Clinical pharmacology and therapeutics Vol. 100; no. 4; p. 362
• Main Authors: Prasad, B, Gaedigk, A, Vrana, M, Gaedigk, R, Leeder, J S, Salphati, L, Chu, X, Xiao, G, Hop, Ceca, Evers, R, Gan, L, Unadkat, J D
• Format: Journal Article
• Language: English
• Published: United States 01.10.2016
• Subjects: Adolescent; Aging - metabolism; ATP Binding Cassette Transporter, Subfamily B - biosynthesis; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; Child; Child, Preschool; Genotype; Humans; Infant; Infant, Newborn; Liver - metabolism; Liver-Specific Organic Anion Transporter 1 - biosynthesis; Liver-Specific Organic Anion Transporter 1 - genetics; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins - biosynthesis; Multidrug Resistance-Associated Proteins - genetics; Neoplasm Proteins - genetics; Organic Anion Transporters, Sodium-Independent - biosynthesis; Organic Cation Transporter 1 - biosynthesis; Polymorphism, Single Nucleotide - genetics; Proteomics; Solute Carrier Organic Anion Transporter Family Member 1B3
• ISSN: 1532-6535
• DOI: 10.1002/cpt.409

Protein expression of major hepatic uptake and efflux drug transporters in human pediatric (n = 69) and adult (n = 41) livers was quantified by liquid chromatography / tandem mass spectroscopy (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.