Background Growth, maturation and physiological modifications are mainly responsible for the difference in pharmacokinetics and pharmacodynamics of drugs ob-served between adults and children, especially neonates. Ontogeny of drug metabolising enzymes and transport-ers play an important role in drugs inter-individual phar-macokinetic variability in this population. Data on neona-tal developmental pharmacology remain very limited.
Neocord aims to characterise mRNA expression of the main cytochromes and transporters involved in the phar-macokinetics and pharmacodynamics of drugs in twin newborns, using umbilical cord blood, according to iden-tified covariates such as genetic background, pregnancy environment, gestational age, sex, maternal pathologies and treatments, etc. A population of twins will allow a precise comparison of individuals with different or identi-cal genetic background.
Methods Umbilical cord blood samples (2.5 ml) were col-lected from women pregnant with twins, both dizygotic and monozygotic, in the maternity ward of Robert-Debré Hospital using PaxGene Blood RNA tubes. Isolation and purification of total RNA from the blood samples was performed using the PAXgene Blood RNA kit with sub-sequent RNA reverse transcription (RT-PCR). Amplification of DNA and gene expression profiling was performed by real-time polymerase chain reaction (qPCR) using Ap-plied Biosystems TaqMan gene expression assay tech-nology. Expression of the 18S ribosomal reference gene was used as internal control for normalisation of expres-sion profiles. A large panel of drug metabolising enzymes and transporters genes was quantified: cytochrome P450 system (n=12), UGT family (n=6), transporters (n=3) and TPMT. Relative gene expression levels between the differ-ent samples were calculated using the ΔΔCt method.
Results Fifty umbilical cord blood samples (32 males and 18 females) from 25 women pregnant with twins, deliv-ering between April 2015 and March 2017, were collect-ed. Median age of the women was 33.2 years (23.2–49.5) and median gestational age at delivery was 37.3 weeks of amenorrhea (34.4–39.6). Nineteen women delivered at term and 6 delivered before 37 weeks. Five women had a monochorionic diamniotic pregnancy and 20 women had a dichorionic diamniotic pregnancy. Monochorionic twins were assumed to be monozygotic (n=10) and dif-ferent-sex twins as dizygotic (n=20). Zygosity of the 20 same-sex dichorionic twins could not be assessed.
Preliminary results were obtained after analysis of 30 cord blood samples. Females (n=12) and males (n=18) showed no differences of weight or gestational age at birth. From these 15 twins pairs: UGT1A6 and UGT2B7 expressions were not found in umbilical cord blood samples while others were expressed at different levels. Gene expression was different between newborn genders (p<0.05) for 5 genes: CYP2A6 (p=0.035), CYP2C9 (p=0.032), CYP3A4 (p=0.005), UGT1A3 (0.035), UGT1A9 (p=0.039), females having greater expressions of all of them.
Conclusion Identification of differences in protein ex-pression profiles will allow a better understanding of the pharmacokinetics and pharmacodynamics variability of drugs in the newborn. Such factors will help improving neonatal care and define appropriate dose regimens in the neonatal population.
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