title: Concentrations of carbamazepine and carbamazepine-10,11-epoxide in maternal and umbilical cord blood at birth: Influence of co-administration of valproic acid or enzyme-inducing antiepileptic drugs.
abstract: BACKGROUND
  Carbamazepine is one of the three most frequently prescribed antiepileptic drugs in pregnancy. However, data relating to both carbamazepine and carbamazepine-10,11-epoxide transplacental passage remain sparse.
  
  
  METHODS
  We have analysed in a cohort of 114 women carbamazepine and carbamazepine-10,11-epoxide levels in maternal and umbilical cord serum at birth during 25 years retrospectively. The carbamazepine maternal apparent oral clearance, ratio of the umbilical cord/maternal level and ratio of the carbamazepine-10,11-epoxide/carbamazepine ratio were estimated. The influence of co-medication with valproic acid or enzyme-inducing antiepileptic drugs was evaluated.
  
  
  RESULTS
  The maternal carbamazepine levels varied from 0.6 to 11.8mg/L (carbamazepine-10,11-epoxide 0.1-2.5mg/L) and in umbilical cord between 0.1 and 10.5mg/L (carbamazepine-10,11-epoxide 0.1-2.2mg/L). The ratio the of umbilical cord/maternal level of carbamazepine ranged from 0.03 to 2.23 (median 0.80) and of carbamazepine-10,11-epoxide between 0.17 and 2.00 (median 0.83). Concomitant administration with enzyme inducers significantly increased the maternal apparent oral clearance by approximately 50% and co-administration with valproic acid approximately by 70%. Combination with valproic acid significantly increased the rate of carbamazepine-10,11-epoxide to the parent drug both in maternal serum (by approximately 80%) and in umbilical cord (by 100%).
  
  
  CONCLUSIONS
  The data showed the wide interindividual variability of the ratio of the umbilical cord/maternal level of both carbamazepine and carbamazepine-10,11-epoxide. It is the first study showing the significant increase of the ratio of umbilical cord/maternal level of carbamazepine-10,11-epoxide and carbamazepine-10,11-epoxide/carbamazepine ratio not only in maternal serum but also in umbilical cord in addition of valproic acid. The present study demonstrates that a concomitant administration of enzyme-inducing antiepileptics and valproic acid increases the maternal apparent oral clearance of carbamazepine significantly.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medicine, University of Ostrava, Syllabova 19, 703 00 Ostrava, Czech Republic; Department of Clinical Pharmacology, Department of Laboratory Diagnostics, University Hospital Ostrava, 17. listopadu 1790, 708 52 Ostrava, Czech Republic. Electronic address: ivana.kacirova@fno.cz.
authors.forename: Ivana
authors.initials: I
authors.lastname: Kacirova
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medicine, University of Ostrava, Syllabova 19, 703 00 Ostrava, Czech Republic. Electronic address: milan.grundmann@osu.cz.
authors.forename: Milan
authors.initials: M
authors.lastname: Grundmann
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medicine, University of Ostrava, Syllabova 19, 703 00 Ostrava, Czech Republic; Department of Clinical Pharmacology, Department of Laboratory Diagnostics, University Hospital Ostrava, 17. listopadu 1790, 708 52 Ostrava, Czech Republic. Electronic address: hana.brozmanova@fno.cz.
authors.forename: Hana
authors.initials: H
authors.lastname: Brozmanova
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood*; D001774:Blood Chemical Analysis; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy; D005260:Female; D005312:Fetal Blood / Q000737:chemistry*; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000188:drug therapy; D012189:Retrospective Studies; D014635:Valproic Acid / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid; C012227:carbamazepine epoxide
keywords: Carbamazepine; Carbamazepine-10,11-epoxide; Delivery; Drug–drug interaction; Epilepsy; Therapeutic drug monitoring