title: The mechanism of the carbamazepine-valproate interaction in humans.
abstract: OBJECTIVE
  The study investigated the mechanism of the interaction between valproate and carbamazepine which causes raised plasma carbamazepine-10,11-epoxide concentrations with unchanged plasma carbamazepine concentrations. This interaction has usually been attributed to valproate inhibiting epoxide hydrolase, the enzyme that catalyses the biotransformation of carbamazepine-10,11-epoxide to carbamazepine-10,11-trans-diol.
  
  
  METHODS
  Clearances of plasma carbamazepine, carbamazepine-epoxide and carbamazepine-diol to relevant carbamazepine metabolites present in urine were measured under steady-state conditions in 17 adults receiving carbamazepine as anticonvulsant monotherapy, and in 10 adults taking the drug together with valproate.
  
  
  RESULTS
  Plasma carbamazepine-epoxide concentrations were higher, relative to carbamazepine dose, in the co-medicated patients. Plasma apparent clearances of carbamazepine, relative to drug dose, were similar whether or not valproate was taken. Formation clearances of carbamazepine-10,11-trans-diol conjugate, and probably of carbamazepine-10,11-trans-diol, were lower in subjects co-medicated with valproate, and a higher proportion of the carbamazepine dose was excreted in urine as carbamazepine-10,11-epoxide.
  
  
  CONCLUSIONS
  Valproate appears to inhibit the glucuronidation of carbamazepine-10,11-trans-diol, and probably also inhibits the conversion of carbamazepine-10,11-epoxide to this trans-diol derivative, rather than simply inhibiting the latter reaction only.
authors.affiliation: Department of Medicine, The University of Queensland, Royal Brisbane Hospital, Herston, Australia.
authors.forename: I
authors.initials: I
authors.lastname: Bernus
authors.forename: R G
authors.initials: RG
authors.lastname: Dickinson
authors.forename: W D
authors.initials: WD
authors.lastname: Hooper
authors.forename: M J
authors.initials: MJ
authors.lastname: Eadie
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D014635:Valproic Acid / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; C004822:10,11-dihydro-10,11-dihydroxy-5H-dibenzazepine-5-carboxamide; D014635:Valproic Acid; C012227:carbamazepine epoxide