Pregnant women are often complicated with diseases that require treatment with medication.Most drugs administered to pregnant women are off-label without the necessary dose,efficacy,and safety information.Knowledge co...Pregnant women are often complicated with diseases that require treatment with medication.Most drugs administered to pregnant women are off-label without the necessary dose,efficacy,and safety information.Knowledge concerning drug transfer across the placental barrier is essential for understanding fetal drug exposure and hence drug safety and efficacy to the fetus.Transporters expressed in the placenta,including adenosine triphosphate(ATP)-binding cassette efflux transporters and solute carrier uptake transporters,play important roles in determining drug transfer across the placental barrier,leading to fetal exposure to the drugs.In this review,we provide an update on placental drug transport,including in vitro cell/tissue,ex vivo human placenta perfusion,and in vivo animal studies that can be used to determine the expression and function of drug transporters in the placenta as well as placental drug transfer and fetal drug exposure.We also describe how the knowledge of placental drug transfer through passive diffusion or active transport can be combined with physiologically based pharmacokinetic modeling and simulation to predict systemic fetal drug exposure.Finally,we highlight knowledge gaps in studying placental drug transport and predicting fetal drug exposure and discuss future research directions to fill these gaps.展开更多
Background Previous reports indicated that mutations in the adenosine triphosphate （ATP）-binding cassette transporter A3 （ABCA3） cause fatal respiratory failure in term infants, and common ABCA3 gene polymorphism...Background Previous reports indicated that mutations in the adenosine triphosphate （ATP）-binding cassette transporter A3 （ABCA3） cause fatal respiratory failure in term infants, and common ABCA3 gene polymorphisms have been characterized at the population level in Caucasians. But the role of ABCA3 in relation to respiratory distress syndrome （RDS） in newborns has not been evaluated within a Chinese population. The aim of this study was to analyze eight single-nucleotide polymorphisms （SNPs） of the ABCA3 gene, and to assess the ABCA3 gene as a candidate gene for susceptibility to RDS in newborns.Methods Eight SNPs were selected and genotyped in 203 newborns. The data analysis and statistical tests were used for allele frequencies, haplotype and Hardy-Weinberg equilibrium pairwise linkage disequilibrium measures. Results There was a haplotype association with SNP rs313909 and SNP rs170447, but no haplotype association was observed among the newborns with and without RDS （P 〉0.05）. The minor allele frequency （G） of the coding SNP （cSNP） rs323043 （P585P） was significantly increased in preterm infants with RDS.Conclusion There is an association between a synonymous cSNP rs323043 and the development of RDS.展开更多
基金supported by the National Institute on Drug Abuse(Grant P01DA032507)the Eunice Kennedy Shriver National Institute of Child Health and Human Development(Grant R01HD102786)。
文摘Pregnant women are often complicated with diseases that require treatment with medication.Most drugs administered to pregnant women are off-label without the necessary dose,efficacy,and safety information.Knowledge concerning drug transfer across the placental barrier is essential for understanding fetal drug exposure and hence drug safety and efficacy to the fetus.Transporters expressed in the placenta,including adenosine triphosphate(ATP)-binding cassette efflux transporters and solute carrier uptake transporters,play important roles in determining drug transfer across the placental barrier,leading to fetal exposure to the drugs.In this review,we provide an update on placental drug transport,including in vitro cell/tissue,ex vivo human placenta perfusion,and in vivo animal studies that can be used to determine the expression and function of drug transporters in the placenta as well as placental drug transfer and fetal drug exposure.We also describe how the knowledge of placental drug transfer through passive diffusion or active transport can be combined with physiologically based pharmacokinetic modeling and simulation to predict systemic fetal drug exposure.Finally,we highlight knowledge gaps in studying placental drug transport and predicting fetal drug exposure and discuss future research directions to fill these gaps.
基金Correspondence to： DU Li-zhong, Depar This work was supported by a grant from the National Natural Science Foundation of China （No. 81070512）.Acknowledgements： We thank the Neonatal Intensive Care Unit staff for their collaboration for this work. The study was also supported by Zhejiang Key Laboratory for Diagnosis and Therapy of Neonatal Diseases.
文摘Background Previous reports indicated that mutations in the adenosine triphosphate （ATP）-binding cassette transporter A3 （ABCA3） cause fatal respiratory failure in term infants, and common ABCA3 gene polymorphisms have been characterized at the population level in Caucasians. But the role of ABCA3 in relation to respiratory distress syndrome （RDS） in newborns has not been evaluated within a Chinese population. The aim of this study was to analyze eight single-nucleotide polymorphisms （SNPs） of the ABCA3 gene, and to assess the ABCA3 gene as a candidate gene for susceptibility to RDS in newborns.Methods Eight SNPs were selected and genotyped in 203 newborns. The data analysis and statistical tests were used for allele frequencies, haplotype and Hardy-Weinberg equilibrium pairwise linkage disequilibrium measures. Results There was a haplotype association with SNP rs313909 and SNP rs170447, but no haplotype association was observed among the newborns with and without RDS （P 〉0.05）. The minor allele frequency （G） of the coding SNP （cSNP） rs323043 （P585P） was significantly increased in preterm infants with RDS.Conclusion There is an association between a synonymous cSNP rs323043 and the development of RDS.
