Ontogeny of Hepatic Drug Transporters as Quantified by LC-MS/MS Proteomics.
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.
Department of Pharmaceutics, University of Washington, Seattle, Washington, USA. bhagwat@u.washington.edu.
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Prasad
Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA.|School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
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Gaedigk
Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
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Vrana
Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA.|School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
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Gaedigk
Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy, Kansas City, Missouri, USA.|School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
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Leeder
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Sharp & Dohme, Kenilworth, New Jersey, USA.
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Salphati
Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey, USA.
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Chu
Biogen, Cambridge, Massachusetts, USA.
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Xiao
Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Sharp & Dohme, Kenilworth, New Jersey, USA.
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Hop
Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Rahway, New Jersey, USA.
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Evers
Biogen, Cambridge, Massachusetts, USA.
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Gan
Department of Pharmaceutics, University of Washington, Seattle, Washington, USA. jash@u.washington.edu.
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Unadkat
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics; D000293:Adolescent; D000375:Aging / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000096:biosynthesis* / Q000235:genetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis*; D027702:Organic Cation Transporter 1 / Q000096:biosynthesis*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040901:Proteomics; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D027702:Organic Cation Transporter 1; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C116614:ABCG2 protein, human; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C114462:multidrug resistance-associated protein 3