Tuija Heikkinen

Citalopram in pregnancy and lactation.

Although citalopram has gained wide acceptance in the treatment of depression and anxiety disorders, its use during pregnancy and lactation has been poorly characterized. The aim of this study was to examine the efficacy and safety of citalopram in relation to concentrations of citalopram and its metabolites during pregnancy and lactation.

Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation

The aim of this prospective clinical trial was to investigate the pharmacokinetics offluoxetine and its active metabolite, norfluoxetine, during pregnancy, delivery, and lactation in mothers and their infants.

Transfer of proinflammatory cytokines across term placenta.

OBJECTIVE: Increased concentrations of proinflammatory cytokines in amniotic fluid indicate the presence of intra-amniotic inflammation and increase the risk of preterm birth, cerebral palsy, and bronchopulmonary dysplasia. The purpose of this study was to find out if the proinflammatory cytokines, tumor necrosis factor alpha (TNF-&agr;), interleukin (IL)-1&bgr;, and IL-6, transfer across the placenta, and thereby determine whether intra-amniotic inflammatory response, measured from the amniotic fluid, is of maternal or fetal origin. METHODS: Nineteen placentas from healthy women undergoing elective cesarean delivery at term with intact membranes and without labor, were dually perfused ex vivo in an open circulation system for either 30 minutes or 2 hours. Tumor necrosis factor-&agr;, IL-1&bgr;, and IL-6 were added to maternal or fetal circulation in a concentration usually found in chorioamnionitis. As a reference, placentas without added cytokine were also perfused. The concentrations of cytokines were determined by enzyme immunoassays (enzyme-linked immunosorbent assay [ELISA]). RESULTS: After the addition of the cytokine to the arterial perfusate, the venous concentration on the same side of the placenta increased rapidly and reached a plateau at 10 minutes. No transfer of any cytokine in either direction was detected. Some endogenous release of IL-6 was observed in response to the perfusion. CONCLUSION: Proinflammatory cytokines do not cross normal term placenta. LEVEL OF EVIDENCE: II-1

The transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin

Objective To investigate the transplacental transfer of the macrolide antibiotics erythromycin, roxithromycin and azithromycin.

Functional role of P-glycoprotein in the human blood-placental barrier

In vitro and animal experiments suggest that P‐glycoprotein forms a functional barrier between maternal and fetal blood circulation in the placenta, thus protecting the fetus from exposure to xenobiotics during pregnancy. In this study we aimed to characterize the role of P‐glycoprotein in the blood‐placental barrier by use of dually perfused human placenta.

Transplacental transfer of citalopram, fluoxetine and their primary demethylated metabolites in isolated perfused human placenta

Objective To investigate the transplacental transfer and the effects of protein binding on the transfer of citalopram, desmethylcitalopram, fluoxetine and desmethylfluoxetine in the isolated perfused human placenta model.

Placental transfer of quetiapine in relation to P-glycoprotein activity.

Atypical antipsychotic drugs are well tolerated and thus often preferred in women of fertile age; yet the information on their placental transfer and use during the prenatal period is limited. The aim of this study was to study the placental transfer of quetiapine, a widely used atypical antipsychotic, with special reference to the role of the placental transporter protein, P-glycoprotein (P-gp). This was performed in 18 dually perfused placentas, using the well established P-gp inhibitors PSC833 (valspodar) and GG918 to inhibit the function of P-gp. We also aimed to clarify the significance of two potentially functional ABCB1 single nuclear polymorphisms (SNPs), 2677G>T/A and 3435C>T, on the transplacental transfer (TPT) of quetiapine. The placental transfer of quetiapine in the control group as measured by TPTAUC % (absolute fraction of the dose crossing placenta) was 3.7%, which is 29% less than the transfer of the freely diffusible antipyrine, which was 5.2%. The P-gp inhibitors had no significant effect on the transfer of quetiapine as measured by TPTAUC % (P = 0.77). No correlation was found between the transplacental transfer of quetiapine (TPTAUC %) and placental P-gp expression (P = 0.61). The 3435T allele in exon 26 was associated with significantly higher placental transfer of quetiapine (P = 0.04). We conclude that quetiapine passes the human placenta but that the blood—placental barrier partially limits the transplacental transfer of quetiapine. Administration of P-gp inhibiting drugs with quetiapine is not likely to increase fetal exposure to quetiapine, although the ABCB1 C3435T polymorphism may contribute to inter-individual variation in fetal exposure to quetiapine.

Influence of adenosine triphosphate and ABCB1 (MDR1) genotype on the P-glycoprotein-dependent transfer of saquinavir in the dually perfused human placenta

Background: The ATP-dependent drug-efflux pump, P-glycoprotein (P-gp) encoded by ABCB1 (MDR1), plays a crucial role in several tissues forming blood–tissue barriers. Absence of a normally functioning P-gp can lead to a highly increased tissue penetration of a number of clinically important drugs. Methods: We have studied the dose–response effect of exogenous ATP on the placental transfer of the well-established P-gp substrate saquinavir in 17 dually perfused human term placentas. We have also studied the influence of the ABCB1 polymorphisms 2677G>T/A and 3435C>T on placental P-gp expression (n = 44) and the transfer (n = 16) of saquinavir. Results: The present results indicate that the addition of exogenous ATP to the perfusion medium does not affect the function of P-gp as measured by saquinavir transfer across the human placenta. The variant allele 3435T was associated with significantly higher placental P-gp expression than the wild-type alleles. However, neither polymorphism affected placental transfer of saquinavir nor there was any correlation between P-gp expression and saquinavir transfer. Conclusions: Our results indicate that addition of exogenous ATP is not required for ATP-dependent transporter function in a dually perfused human placenta. Although the ABCB1 polymorphism 3435C>T altered the expression levels of P-gp in the human placenta, this did not have any consequences on P-gp–mediated placental transfer of saquinavir.

Transfer of repaglinide in the dually perfused human placenta and the role of organic anion transporting polypeptides (OATPs).

OBJECTIVES Our aim was to investigate the placental transfer of repaglinide by ex vivo placental perfusion experiment. In addition, the involvement of the active organic anion transporters (OATP1B1, OATP1B3 and OATP2B1) was studied by assessing the single nucleotide polymorphisms (SNPs) in genes (SLCO1B1, SLCO1B3 and SLCO2B1) encoding OATPs. STUDY DESIGN Fifteen placentas were obtained after delivery and a 2-h non-recirculating perfusion of a single placental cotyledon was performed to study maternal-to-fetal and fetal-to-maternal transport of repaglinide by using antipyrine as a reference of passive-diffusion transfer compound. Genotyping was performed for all placentas. RESULTS Maternal-to-fetal transfer of repaglinide and antipyrine were 1.5% and 13.2%, respectively, and fetal-to-maternal transfers were 6.7% and 40.3%, respectively. Fetal-to-maternal transfer of repaglinide was statistically significantly higher than maternal-to-fetal transfer (P<0.0001). The number of placentas was not sufficient for proper statistical analysis, but the fetal-to-maternal transfer seemed to be affected by the SLCO1B3 polymorphism. CONCLUSIONS The placental transfer of repaglinide from mother to fetus was low. Since a higher transfer rate of repaglinide was observed in fetal-to-maternal than maternal-to-fetal direction, active transport by OATP-transporters may be an important factor in fetal exposure to repaglinide.

The effect of probenecid and MK-571 on the feto-maternal transfer of saquinavir in dually perfused human term placenta.

Human placenta, particularly the blood-placenta barrier, with various transporters has crucial role to protect the fetus and, on the other hand, to facilitate movement of compounds towards the fetal circulation. This study aimed to characterize the role of basal transporters of the syncytiotrophoblast, which appear to be yet less studied, in the fetal-to-maternal transfer of saquinavir by use of dually perfused human placentas. A dual perfusion of human placenta was performed to study effect of MK-571 and probenecid, inhibitors of the MRP1 and OATP transporters, expressed in the basal trophoblast membrane, on the transfer of saquinavir. The fetal-to-maternal placental transfer of saquinavir in the control group as measured by TPT(AUC)% (absolute fraction of the dose crossing placenta) was 14.0%, which is 73% less than the transfer of the freely diffusible antipyrine. The two inhibitors, MK-571 and probenecid caused a non-significant (P = 0.34 for ANOVA) reduction of 43% and 24%, respectively, in the mean amount of saquinavir transferred from the fetal to the maternal side. MK-571 also somewhat (by 31%) reduced the TPT(AUC)% of antipyrine, but this finding did not reach statistical significance (P = 0.25). Neither of the employed inhibitors had an effect on the placental transfer index of saquinavir transfer (P = 0.77). The present results indicated lack of significant effect by MK-571 and probenecid on the fetal-to-maternal transfer of saquinavir and suggest that MRP1 and, possibly, OATP2B1 do not play a significant role in the fetal-to-maternal transfer of saquinavir.