Influence of MRP3 Genetics and Hepatic Expression Ontogeny for Morphine Disposition in Neonatal and Pediatric Patients.
Adolescent
Adult
Age Factors
Child
Child, Preschool
Genetic Variation
Genotype
Humans
Infant
Infant, Newborn
Liver
/ metabolism
Morphine
/ metabolism
Multidrug Resistance-Associated Proteins
/ biosynthesis
Octamer Transcription Factor-1
/ biosynthesis
Polymorphism, Single Nucleotide
Retrospective Studies
Tissue Distribution
Young Adult
ontogeny
opioid use
pediatrics (PED)
pharmacogenetics/pharmacogenomics
transporters
Journal
Journal of clinical pharmacology
ISSN: 1552-4604
Titre abrégé: J Clin Pharmacol
Pays: England
ID NLM: 0366372
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
09
11
2019
accepted:
26
01
2020
pubmed:
25
2
2020
medline:
10
7
2021
entrez:
25
2
2020
Statut:
ppublish
Résumé
We have previously reported the influences of OCT1 ontogeny and genetic variation on morphine clearance in neonatal and pediatric patients. In the latter study, plasma morphine-glucuronide levels correlated with patient genotype for the rs4793665 single-nucleotide polymorphism (SNP) at the locus of MRP3, an efflux transporter of morphine glucuronides between hepatocytes and circulating blood. The link between MRP3 activity and overall morphine clearance has not been thoroughly investigated however, and the developmental profile of hepatic MRP3 protein expression remains thinly defined between neonates and adults. In the current study, previously determined morphine clearance values for neonatal (24-58 weeks postmenstrual age, N = 57) and pediatric (5-16 years, n = 85) patients were reanalyzed for correlation to the SNP genotype of patient rs4793665. Among OCT1 wild-type patients, pediatric morphine clearance showed a significant decreasing trend by MRP3 genotypes in the order of CC > CT > TT (P = .014), whereas for neonates, an identical but nonsignificant trend was observed. Pharmacogenetic differences in MRP3 and OCT1 ontogeny were evaluated by Western blot of hepatic membrane fractions from 50 subjects aged 1 day postnatal to 33 years old. Hepatic MRP3 protein level did not vary by rs4793665 genotype, and followed an atypical developmental pattern of increase up to 1-2 years of age, thereafter decreasing during preadolescence before increasing again to adult levels at maturity (17-33 years). By comparison, OCT1 expression was significantly decreased in OCT1 *1/*3 genotyped patients older than 1 year and followed a trajectory consistent with prior studies. Our results suggest that consideration of MRP3 pharmacogenetics and ontogeny may aid in identifying pediatric patients having different/atypical morphine requirements.
Substances chimiques
Multidrug Resistance-Associated Proteins
0
Octamer Transcription Factor-1
0
POU2F1 protein, human
0
multidrug resistance-associated protein 3
1YV0492L5Z
Morphine
76I7G6D29C
Banques de données
ClinicalTrials.gov
['NCT01140724']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
992-998Subventions
Organisme : NICHD NIH HHS
ID : R01 HD089458
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001425
Pays : United States
Organisme : NICHD NIH HHS
ID : R21 HD095418
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD069054
Pays : United States
Informations de copyright
© 2020, The American College of Clinical Pharmacology.
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