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 transporters 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 trans-porters genes was quantified: cytochrome P450 system (n=12), UGT family (n=6), transporters (n=3) and TPMT.
Relative gene expression levels between the different samples were calculated using the ΔΔCt method.
Results Fifty umbilical cord blood samples (32 males and 18 females) from 25 women pregnant with twins, deliver-ing between April 2015 and March 2017, were collected.
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. Further analyses are currently ongoing.
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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