Proteomics of human liver membrane transporters: a focus on fetuses and newborn infants

Groen, Bianca D van; Steeg, Evita van de; Mooij, Miriam G.; Lipzig, Marola M.H. van; Koning, Barbara A E de; Verdijk, Robert M.; Wortelboer, Heleen M.; Gaedigk, Roger; Bi, Chengpeng; Leeder, J. Steven; Schaik, Ron H.N. van; Rosmalen, Joost van; Tibboel, Dick; Vaes, Wouter H. J.; Wildt, Saskia N. de

doi:10.1016/j.ejps.2018.08.042

Cited by 39 publications

(88 citation statements)

References 39 publications

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“… OCT1 : As previously reported, OCT1 mRNA levels in pediatric livers appeared to be comparable to those in adult livers . Nonetheless, OCT1 protein levels have been shown to undergo an age‐dependent increase . This was supported by a recently published clinical study in neonates who were admitted to the neonatal intensive care unit where postmenstrual age as well as OCT1 genotype impacted the PK of the OCT1 substrate morphine .…”

Section: Ontogeny Of Membrane Transporterssupporting

confidence: 68%

“…In their sample set van Groen et al found that the OATP1B1 expression was significantly higher in the fetal livers compared with that in term neonatal livers. The protein expressions in infants, children, and adults were similar . OATP1B1 is highly polymorphic.…”

Section: Ontogeny Of Membrane Transportersmentioning

confidence: 86%

“…Notably, in the >1‐year‐old cohort, OATP1B1 expression was about 2.5‐fold higher in samples from donors with *14/*1A than from those with *15/*1A . OATP1B3 : Similar to OATP1B1, mRNA expression of OATP1B3 was reported to be much lower in fetuses, neonates, and infants compared with adults . Although proteomics data in 1 study showed that OATP1B3 expression was not associated with age, another illustrated that the expression of the transporter was subjected to age‐dependent increase, and by 6 months of age, similar to OCT1, the protein expression would have reached 50% of the adult level OATP2B1 : mRNA levels of OAT2B1 were significantly higher in adult livers compared with those in livers from fetus at gestational age 18‐23 weeks .…”

Section: Ontogeny Of Membrane Transportersmentioning

confidence: 96%

“…In addition, quantitative proteomics via liquid chromatography/tandem mass spectrometry has been increasingly utilized to measure the absolute protein abundance of these transporters, allowing the quantification of many transporters in only a small amount of tissue. Proteomics data generated from 2 independent laboratories complemented each other in terms of age range of the samples and provided a more complete picture of the developmental patterns of hepatic transporters with higher confidence than what was known previously . In 1 study the protein abundance of 11 hepatic transporters was measured in approximately 69 postmortem tissue samples that covered the whole pediatric age range (4 neonates, 19 infants, 32 children, and 14 adolescents) and in 41 adult samples (>16 years old) .…”

Section: Ontogeny Of Membrane Transportersmentioning

confidence: 99%

“…In 1 study the protein abundance of 11 hepatic transporters was measured in approximately 69 postmortem tissue samples that covered the whole pediatric age range (4 neonates, 19 infants, 32 children, and 14 adolescents) and in 41 adult samples (>16 years old) . In another study the absolute protein expression of 13 liver transporters was quantified in a pediatric cohort with a focus on the fetus and newborn up to postnatal 18 weeks of age that consisted of 62 pediatric tissue samples (36 fetuses, 12 premature newborns, 10 term newborns, 4 pediatric patients, and 8 tissue samples from adults) . The findings in these 2 studies and other previous studies are discussed below.…”

Section: Ontogeny Of Membrane Transportersmentioning

confidence: 99%

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Incorporating Ontogeny in Physiologically Based Pharmacokinetic Modeling to Improve Pediatric Drug Development: What We Know About Developmental Changes in Membrane Transporters

Cheung

Groen

Burckart

et al. 2019

The Journal of Clinical Pharma

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Developmental changes in the biological processes involved in the disposition of drugs, such as membrane transporter expression and activity, may alter the drug exposure and clearance in pediatric patients. Physiologically based pharmacokinetic (PBPK) models take these age‐dependent changes into account and may be used to predict drug exposure in children. As a result, this mechanistic‐based tool has increasingly been applied to improve pediatric drug development. Under the Prescription Drug User Fee Act VI, the US Food and Drug Administration has committed to facilitate the advancement of PBPK modeling in the drug application review process. Yet, significant knowledge gaps on developmental biology still exist, which must be addressed to increase the confidence of prediction. Recently, more data on ontogeny of transporters have emerged and supplied a missing piece of the puzzle. This article highlights the recent findings on the ontogeny of transporters specifically in the intestine, liver, and kidney. It also provides a case study that illustrates the utility of incorporating this information in predicting drug exposure in children using a PBPK approach. Collaborative work has greatly improved the understanding of the interplay between developmental physiology and drug disposition. Such efforts will continue to be needed to address the remaining knowledge gaps to enhance the application of PBPK modeling in drug development for children.

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