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

B Prasad; A Gaedigk; M Vrana; R Gaedigk; J S Leeder; L Salphati; X Chu; G Xiao; Ceca Hop; R Evers; L Gan; J D Unadkat

doi:10.1002/cpt.409

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

Clin Pharmacol Ther. 2016 Oct;100(4):362-70. doi: 10.1002/cpt.409. Epub 2016 Aug 13.

Authors

B Prasad¹, A Gaedigk^{2

3}, M Vrana⁴, R Gaedigk^{2

3}, J S Leeder^{2

3}, L Salphati⁵, X Chu⁶, G Xiao⁷, Ceca Hop⁵, R Evers⁶, L Gan⁷, J D Unadkat⁸

Affiliations

¹ Department of Pharmaceutics, University of Washington, Seattle, Washington, USA. bhagwat@u.washington.edu.
² Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA.
³ School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
⁴ Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
⁵ Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Sharp & Dohme, Kenilworth, New Jersey, USA.
⁶ Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey, USA.
⁷ Biogen, Cambridge, Massachusetts, USA.
⁸ Department of Pharmaceutics, University of Washington, Seattle, Washington, USA. jash@u.washington.edu.

PMID: 27301780
PMCID: PMC5017908
DOI: 10.1002/cpt.409

Abstract

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.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / biosynthesis*
ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics
Adolescent
Aging / metabolism*
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

Substances

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily G, Member 2
Liver-Specific Organic Anion Transporter 1
Multidrug Resistance-Associated Protein 2
Multidrug Resistance-Associated Proteins
Neoplasm Proteins
Organic Anion Transporters, Sodium-Independent
Organic Cation Transporter 1
SLCO1B1 protein, human
SLCO1B3 protein, human
Solute Carrier Organic Anion Transporter Family Member 1B3
multidrug resistance-associated protein 3

Abstract

MeSH terms

Substances

Grants and funding