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.

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 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 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
  • multidrug resistance-associated protein 2