title: Lamotrigine and its N2-glucuronide during pregnancy: the significance of renal clearance and estradiol.
abstract: OBJECTIVE
  To investigate the physiological mechanisms behind the pronounced decline of lamotrigine (LTG) serum concentrations during pregnancy.
  
  
  METHODS
  Serum and urine concentrations of LTG and its main metabolite, LTG-N2-glucuronide (LTG-GLUC), were measured monthly in 21 pregnancies of 19 women using LTG. Simultaneously, a panel of biochemical variables was monitored to evaluate liver and kidney function and possible hemodilution effects. Pharmacokinetic parameters were calculated once at baseline and once in gestational month 8.
  
  
  RESULTS
  Initially, LTG and LTG-GLUC serum concentrations fell simultaneously by 27% and 38%, respectively (gestational month 2). Subsequently, the ratio of the LTG-GLUC/LTG serum concentrations increased gradually, correlating strongly with rising serum estradiol concentrations. In gestational month 8, the ratio was 164% higher than at baseline. At that time, LTG total clearance had increased by 118%, and the amount of unchanged LTG in urine had dropped by 40% while the amount of LTG-GLUC had increased by a corresponding 37%.
  
  
  CONCLUSIONS
  The simultaneous decline of LTG and LTG-GLUC serum concentrations in early pregnancy suggests that in this phase, increased renal blood flow is the major cause. After gestational month 2, estradiol-induced glucuronidation of LTG becomes more important, leading to a further fall of LTG serum concentrations and a gradual rise of the LTG-GLUC/LTG-ratio through the remaining pregnancy. An expanded volume of distribution may also contribute to reduced LTG serum concentrations in pregnancy.
authors.affiliation: Department of Clinical Pharmacology, St. Olavs University Hospital, 7006 Trondheim, Norway; Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7489 Trondheim, Norway.
authors.forename: Arne
authors.initials: A
authors.lastname: Reimers
authors.affiliation: Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7489 Trondheim, Norway.
authors.forename: Grethe
authors.initials: G
authors.lastname: Helde
authors.affiliation: Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7489 Trondheim, Norway; Department of Neurology and Clinical Neurophysiology, St. Olavs University Hospital, 7006 Trondheim, Norway.
authors.forename: Geir
authors.initials: G
authors.lastname: Bråthen
authors.affiliation: Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7489 Trondheim, Norway; Department of Neurology and Clinical Neurophysiology, St. Olavs University Hospital, 7006 Trondheim, Norway.
authors.forename: Eylert
authors.initials: E
authors.lastname: Brodtkorb
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000097:blood / Q000627:therapeutic use* / Q000652:urine; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D004958:Estradiol / Q000097:blood*; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D010045:Outpatients; D049590:Postpartum Period / Q000097:blood / Q000652:urine; D011247:Pregnancy; D011446:Prospective Studies; D012079:Renal Circulation / Q000187:drug effects*; D014227:Triazines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000652:urine; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D014227:Triazines; C074259:lamotrigine 2-N-glucuronide; D004958:Estradiol; D000077213:Lamotrigine