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

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

Author information

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.

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.

PMID:
27301780
PMCID:
PMC5017908
DOI:
10.1002/cpt.409
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Conflict of Interest/Disclosure There is no conflict of interest

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