title: Rivaroxaban transfer across the dually perfused isolated human placental cotyledon.
abstract: OBJECTIVE
  The purpose of this study was to determine the rate and extent of rivaroxaban transfer across the term human placenta and determine whether passive diffusion was the primary mechanism involved in this transfer.
  
  
  METHODS
  The transplacental pharmacokinetics of rivaroxaban was determined with the ex-vivo placenta perfusion model. Rivaroxaban was added to the maternal or fetal circulation only (250 ng/mL). Additional experiments were conducted under equilibrative conditions with the addition of rivaroxaban to both the maternal and fetal circulations (250 ng/mL). Rivaroxaban concentrations were measured with the use of liquid chromatography-tandem mass spectrometry.
  
  
  RESULTS
  There was rapid transfer of rivaroxaban across the human placenta in both the maternal-to-fetal and fetal-to-maternal directions, as evidenced by transfer ratios of 0.69 (interquartile range, 0.58-0.73; n = 5) and 0.69 (interquartile range, 0.67-0.71; n = 2), respectively, after 3 hours. Under equilibrative conditions (n = 2), rivaroxaban concentrations remained relatively constant, which suggests that rivaroxaban crosses the placenta down a concentration gradient.
  
  
  CONCLUSIONS
  This is the first direct evidence of rivaroxaban transfer across the term human placenta from both the mother-to-fetus and fetus-to-mother directions. Our results document that unbound rivaroxaban rapidly crosses the placental barrier via passive diffusion. However, because rivaroxaban is highly bound to plasma proteins (up to 95%), this suggests that the amount of unbound drug that may reach the fetus is likely much lower. Additional studies will need to explore its safety before administering rivaroxaban to a pregnant woman.
authors.affiliation: Motherisk Program, Division of Clinical Pharmacology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Priya
authors.initials: P
authors.lastname: Bapat
authors.affiliation: Motherisk Program, Division of Clinical Pharmacology, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Leonardo Santos Ribeiro
authors.initials: LS
authors.lastname: Pinto
authors.affiliation: Motherisk Program, Division of Clinical Pharmacology, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Angelika
authors.initials: A
authors.lastname: Lubetsky
authors.affiliation: Department of Obstetrics and Gynecology, St. Michael's Hospital, Toronto, ON, Canada.
authors.forename: Howard
authors.initials: H
authors.lastname: Berger
authors.affiliation: Motherisk Program, Division of Clinical Pharmacology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address: gidiup_2000@yahoo.com.
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D001775:Blood Circulation / Q000502:physiology; D002853:Chromatography, Liquid; D065427:Factor Xa Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D005333:Fetus / Q000502:physiology; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D010920:Placenta / Q000098:blood supply / Q000378:metabolism*; D011247:Pregnancy; D000069552:Rivaroxaban / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry
chemical_list: D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban
keywords: anticoagulant; perfusion; placenta; pregnancy; rivaroxaban