title: Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta.
abstract: OBJECTIVE
  To assess the transplacental pharmacokinetics at term of the oral thrombin inhibitor, dabigatran, and its prodrug, dabigatran etexilate mesylate, to estimate fetal drug exposure.
  
  
  METHODS
  Placentae were obtained with informed consent after cesarean delivery of healthy term pregnancies in Toronto, Ontario, Canada. The transplacental transfer of dabigatran and dabigatran etexilate mesylate was separately assessed using the ex vivo dual perfusion of an isolated human placental cotyledon. Dabigatran, at a concentration of 35 ng/mL, was added to the maternal circulation at the start of the experimental phase. Maternal and fetal samples were taken throughout the preexperimental (1 hour) and experimental (3 hours) phases for measurement of dabigatran and markers of placental viability. Separate placenta perfusions with dabigatran etexilate mesylate were conducted at an initial maternal concentration of 3.5 ng/mL. Dabigatran and dabigatran etexilate mesylate were measured using liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  There was slower transfer of dabigatran compared with antipyrine from the maternal-to-fetal circulation, because the median fetal-to-maternal concentration ratio was 0.33 (interquartile range 0.29-0.38) after 3 hours (n=3). The prodrug, dabigatran etexilate mesylate, had limited placental transfer as characterized by a fetal-to-maternal ratio of 0.17 (interquartile range 0.15-0.17) after 3 hours (n=3). Placental viability markers for all perfusions were within normal ranges.
  
  
  CONCLUSIONS
  This report provides direct evidence of the transfer of dabigatran and its prodrug across the term human placenta from the mother to the fetus. From a clinical perspective, these data suggest that, pending further study, dabigatran should not be used for anticoagulation of pregnant women, because the drug may have an adverse effect on fetal blood coagulation.
authors.affiliation: Motherisk Program, Division of Clinical Pharmacology, the Hospital for Sick Children, the Departments of Pharmacology and Toxicology and Pediatrics, University of Toronto, and the Department of Obstetrics and Gynecology, St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Priya
authors.initials: P
authors.lastname: Bapat
authors.forename: Reuven
authors.initials: R
authors.lastname: Kedar
authors.forename: Angelika
authors.initials: A
authors.lastname: Lubetsky
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Matlow
authors.forename: Katarina
authors.initials: K
authors.lastname: Aleksa
authors.forename: Howard
authors.initials: H
authors.lastname: Berger
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D000991:Antithrombins / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000493:pharmacokinetics*; D000075202:Contraindications; D000069604:Dabigatran; D005260:Female; D005333:Fetus / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D010477:Perfusion; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic / Q000188:drug therapy; D011355:Prodrugs / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000991:Antithrombins; D001562:Benzimidazoles; D011355:Prodrugs; D011725:Pyridines; D015091:beta-Alanine; D000069604:Dabigatran