TY - JOUR
T1 - Maternal use of drug substrates of placental transporters and the effect of transporter-mediated drug interactions on the risk of congenital anomalies
AU - Daud, Aizati N. A.
AU - Bergman, Jorieke E. H.
AU - Oktora, Monika P.
AU - Kerstjens-Frederikse, Wilhelmina S.
AU - Groen, Henk
AU - Bos, Jens H.
AU - Hak, Eelko
AU - Wilffert, Bob
PY - 2017/3/13
Y1 - 2017/3/13
N2 - BackgroundA number of transporter proteins are expressed in the placenta, and they facilitate the placental transfer of drugs. The inhibition of P-glycoprotein (P-gp) was previously found to be associated with an increase in the risk of congenital anomalies caused by drug substrates of this transporter. We now explore the role of other placental transporter proteins.MethodsA population-based case-referent study was performed using cases with congenital anomalies (N = 5,131) from EUROCAT Northern Netherlands, a registry of congenital anomalies. The referent population (N = 31,055) was selected from the pregnancy IADB. nl, a pharmacy prescription database.ResultsTen placental transporters known to have comparable expression levels in the placenta to that of P-gp, were selected in this study. In total, 147 drugs were identified to be substrates, inhibitors or inducers, of these transporters. Fifty-eight of these drugs were used by at least one mother in our cases or referent population, and 28 were used in both. The highest user rate was observed for the substrates of multidrug resistance-associated protein 1, mainly folic acid (6% of cases, 8% of referents), and breast cancer resistance protein, mainly nitrofurantoin (2.3% of cases, 2.9% of referents). In contrast to P-gp, drug interactions involving substrates of these transporters did not have a significant effect on the risk of congenital anomalies.ConclusionsSome of the drugs which are substrates or inhibitors of placental transporters were commonly used during pregnancy. No significant effect of transporter inhibition was found on fetal drug exposure, possibly due to a limited number of exposures.
AB - BackgroundA number of transporter proteins are expressed in the placenta, and they facilitate the placental transfer of drugs. The inhibition of P-glycoprotein (P-gp) was previously found to be associated with an increase in the risk of congenital anomalies caused by drug substrates of this transporter. We now explore the role of other placental transporter proteins.MethodsA population-based case-referent study was performed using cases with congenital anomalies (N = 5,131) from EUROCAT Northern Netherlands, a registry of congenital anomalies. The referent population (N = 31,055) was selected from the pregnancy IADB. nl, a pharmacy prescription database.ResultsTen placental transporters known to have comparable expression levels in the placenta to that of P-gp, were selected in this study. In total, 147 drugs were identified to be substrates, inhibitors or inducers, of these transporters. Fifty-eight of these drugs were used by at least one mother in our cases or referent population, and 28 were used in both. The highest user rate was observed for the substrates of multidrug resistance-associated protein 1, mainly folic acid (6% of cases, 8% of referents), and breast cancer resistance protein, mainly nitrofurantoin (2.3% of cases, 2.9% of referents). In contrast to P-gp, drug interactions involving substrates of these transporters did not have a significant effect on the risk of congenital anomalies.ConclusionsSome of the drugs which are substrates or inhibitors of placental transporters were commonly used during pregnancy. No significant effect of transporter inhibition was found on fetal drug exposure, possibly due to a limited number of exposures.
KW - RESISTANCE PROTEIN BCRP/ABCG2
KW - RNA EXPRESSION PROFILES
KW - P-GLYCOPROTEIN
KW - MESSENGER-RNA
KW - MEMBRANE TRANSPORTERS
KW - PREGNANCY
KW - EXPOSURE
KW - PHARMACOKINETICS
KW - DISPOSITION
KW - METABOLISM
U2 - 10.1371/journal.pone.0173530
DO - 10.1371/journal.pone.0173530
M3 - Article
C2 - 28288183
VL - 12
JO - PLOS-One
JF - PLOS-One
SN - 1932-6203
IS - 3
M1 - e0173530
ER -