title: Irinotecan chemotherapy during valproic acid treatment: pharmacokinetic interaction and hepatotoxicity.
abstract: OBJECTIVE
  Because of its supposed inhibiting capacities of uridine-diphosphate glucuronosyltransferase 1A (UGT1A)-mediated glucuronidation in rats, the antiepileptic drug valproic acid has been investigated as modulator of irinotecan-induced delayed-type diarrhea in rats. Here, we report on the pharmacokinetic and pharmacodynamic effects of this combination in a cancer patient.
  
  
  METHODS
  A patient who used valproic acid was administered irinotecan (600 mg). To investigate dose-limiting hepatotoxicity encountered during the first course, which was clinically attributed to a supposed higher exposure to the active irinotecan metabolite SN-38, valproic acid was tapered off. Blood samples for pharmacokinetic purposes were drawn during a course with and a course without concomitant valproic acid. Plasma-levels of irinotecan, SN-38, and SN-38G were determined using HPLC-assays.
  
  
  RESULTS
  When irinotecan was combined with valproic acid, the exposure to SN-38 was 41% lower. Additionally, reversible elevations of the liver enzyme tests were noted. In particular, seven days after irinotecan administration gammaGT and transaminase levels raised up to 5.3-11.3 times the ULN (CTCAE grade 3).
  
  
  CONCLUSIONS
  Valproic acid-induced plasma protein binding displacement and/or metabolic modulation of enzymes and drug transporters involved in irinotecan disposition may explain the reduced exposure to SN-38 in the presence of valproic acid. Given the herewith-coupled potential undertreatment, patients should firstly switch to another antiepileptic drug not known to interfere with irinotecan treatment. Additionally, this particular combination should not be implemented in clinical studies without simultaneously adjusting the irinotecan dose, and the risk of (severe) hepatotoxicity should be considered when designing protocols studying valproic acid (as histone deacetylase-inhibitor) in combination with other (anticancer) drugs.
authors.affiliation: Department of Medical Oncology, Erasmus MC University Medical Center-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. f.a.dejong@erasmusmc.nl
authors.forename: Floris A
authors.initials: FA
authors.lastname: de Jong
authors.forename: Jessica M
authors.initials: JM
authors.lastname: van der Bol
authors.forename: Ron H J
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathôt
authors.forename: Jos J E M
authors.initials: JJ
authors.lastname: Kitzen
authors.forename: Martin J
authors.initials: MJ
authors.lastname: van den Bent
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005965:Glucuronates / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D008099:Liver / Q000187:drug effects*; D008875:Middle Aged; D008954:Models, Biological; D000637:Transaminases / Q000378:metabolism; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000099148:UGT1A1 Enzyme
chemical_list: D000970:Antineoplastic Agents; D002166:Camptothecin; D005965:Glucuronates; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000637:Transaminases; D014635:Valproic Acid; D000099148:UGT1A1 Enzyme; C114685:7-ethyl-10-hydroxycamptothecin beta-glucuronide