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

Autor: Roger Gaedigk, J. S. Leeder, Jashvant D. Unadkat, Bhagwat Prasad, L. Salphati, L. Gan, Guangqing Xiao, Cornelis E. C. A. Hop, Marc Vrana, Andrea Gaedigk, Raymond Evers, Xiaoyan Chu
Rok vydání: 2016
Předmět:
Proteomics
Aging
Physiologically based pharmacokinetic modelling
ATP Binding Cassette Transporter
Subfamily B
Adolescent
Genotype
Organic anion transporter 1
ATP-binding cassette transporter
Organic Anion Transporters
Sodium-Independent
Pharmacology
Polymorphism
Single Nucleotide
030226 pharmacology & pharmacy
Article
Solute Carrier Organic Anion Transporter Family Member 1B3
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
ATP Binding Cassette Transporter
Subfamily G
Member 2
Humans
Pharmacology (medical)
Child
biology
Liver-Specific Organic Anion Transporter 1
Infant
Newborn
Organic Cation Transporter 1
Infant
Transporter
Multidrug Resistance-Associated Protein 2
Neoplasm Proteins
Transport protein
Liver
Child
Preschool
030220 oncology & carcinogenesis
biology.protein
Efflux
Multidrug Resistance-Associated Proteins
Zdroj: Clinical Pharmacology & Therapeutics. 100:362-370
ISSN: 0009-9236
DOI: 10.1002/cpt.409
Popis: 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 (P0.05) 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 livers1 year, tissues harboring SLCO1B1*14/*1A showed 2.5-fold higher (P0.05) 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.
Databáze: OpenAIRE
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