Developmental Changes in Hepatic Organic Cation Transporter OCT1 Protein Expression from Neonates to Children

Abstract

Organic cation transporter 1 (OCT1) plays an important role in the disposition of clinically important drugs, and the capacity of OCT1 activity is presumed to be proportional to the protein expression level in organ tissues. Knowledge of OCT1 protein expression in children, especially neonates and small infants, is currently very limited. Here, we report on the characterization of OCT1 protein expression in neonatal, infant, and pediatric liver samples performed using immunoblot analysis. OCT1 protein expression was detected in liver samples from neonates as early as postnatal days 1 and 2. This youngest group showed significantly lower OCT1 expression normalized by glyceraldehyde-6-phosphate dehydrogenase (values given as means ± S.D. in arbitrary units; 0.03 ± 0.02, n = 7) compared with samples from patients aged 3 to 4 weeks (0.08 ± 0.03, n = 5, P < 0.01), 3 to 6 months (0.23 ± 0.15, n = 7, P < 0.01), 11 months to 1 year (0.42 ± 0.32, n = 6, P < 0.01), and 8 to 12 years (1.00 ± 0.44, n = 7, P < 0.01). These data demonstrate an age-dependent increase in OCT1 expression from birth up to 8 to 12 years of age, and the findings of this study contribute to the understanding of OCT1 functional capacity and its effect upon the disposition of OCT1 substrates in neonates and small infants.

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

“…In line with these observations, O-desmethyltramadol/tramadol metabolic ratios in newborn infants carrying the SLC22A1 low activity genotype were higher than those in infants carrying 2 SLC22A1 wildtype alleles (44 ). Organic Cation OCT1 is expressed from the first postnatal day and increases quickly in the following months (45,46 ), which fits with the found genotype-phenotype correlation.…”

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

“… 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 .…”

PBPK Model of Morphine Incorporating Developmental Changes in Hepatic OCT1 and UGT2B7 Proteins to Explain the Variability in Clearances in Neonates and Small Infants

“…Regarding hepatic OCT1 function, the uptake transporter activity may vary with expression levels of the OCT1 protein. In the neonatal and infant periods, hepatic OCT1 protein expression showed an age‐dependent developmental change, as did hepatic blood flow and UGT2B7. Therefore, these developmental changes may have an impact on morphine PK in neonates and small infants.…”

“…The abundance of OCT1 protein in neonatal liver samples showed large variability. Our previous study showed that the coefficient of variation for OCT1 protein expressions was 38–67% in neonatal liver samples . In order to reduce the predicted large distribution, one possible solution is to identify the variability in OCT1 activity for each genotype, as well as a genotype‐dependent ontogeny profile; which will be considered in a future study.…”

“…Our previous study using PBPK modeling of morphine demonstrated OCT1 and blood flow as important potential contributors to PK variability after intravenous administration in pediatric (6–16 years old) and adult subjects . As for OCT1, an age‐dependent increase in hepatic OCT1 protein expression was determined using pediatric liver tissues . The hepatic blood flow also demonstrated an age‐dependent increase .…”