title: Stability of oxaliplatin in chloride-containing carrier solutions used in hyperthermic intraperitoneal chemotherapy.
abstract: OBJECTIVE
  Oxaliplatin is increasingly becoming the chemotherapeutic drug of choice for the treatment of peritoneal malignancies using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Oxaliplatin is unstable in chloride-containing media, resulting in the use of 5% dextrose as the carrier solution in these procedures. Exposure of the peritoneum to 5% dextrose during perfusion times varying from 30 min to 90 min is associated with serious hyperglycemias and electrolyte disturbances. This can result in significant postoperative morbidity and mortality. In order to find out whether safer, chloride-containing carrier solutions can be used, we report the results of in-vitro analysis of oxaliplatin stability in both chloride-containing and choride-deficient carrier solutions and discuss the implications for oxaliplatin-based CRS-HIPEC procedures.
  
  
  METHODS
  5 mg of oxaliplatin was added to 50 mL of various carrier solutions at 42 °C: 5% dextrose, 0.9% sodium chloride, Ringer lactate, Dianeal(®) PD4 glucose 1.36% solution for peritoneal dialysis and 0.14 M sterile phosphate buffer pH 7.4. Samples were collected at standardized intervals and oxaliplatin concentration was determined using a stability indicating high-performance liquid chromatographic method, coupled to an UV detector (HPLC-UV); oxaliplatin degradation products were identified using HPLC-mass spectometry.
  
  
  RESULTS
  In 5% dextrose, oxaliplatin concentration remained stable over a 2-hour period. Increasing chloride concentrations were associated with increasing degradation rates; however, this degradation was limited to <10% degradation after 30 min (the standard peritoneal perfusion time in most clinical CRS-HIPEC protocols) and <20% degradation after 120 min at 42 °C. In addition, oxaliplatin degradation was associated with the formation of its active drug form [Pt(dach)Cl2].
  
  
  CONCLUSIONS
  The use of chloride-containing carrier solutions for oxaliplatin does not relevantly affect its concentrations under the tested in-vitro conditions. Chloride seems to promote formation of the active cytotoxic drug form of oxaliplatin and therefore could enhance its cytotoxic effect. These data show that more physiological, chloride-containing carrier solutions can be used safely and effectively as a medium for oxaliplatin in CRS-HIPEC procedures.
authors.affiliation: Department of Surgical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Electronic address: a.mehta@nki.nl.
authors.forename: A M
authors.initials: AM
authors.lastname: Mehta
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Van den Hoven
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: M J X
authors.initials: MJ
authors.lastname: Hillebrand
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Nuijen
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Surgical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: V J
authors.initials: VJ
authors.lastname: Verwaal
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D002712:Chlorides / Q000737:chemistry*; D065426:Cytoreduction Surgical Procedures; D004355:Drug Stability; D006979:Hyperthermia, Induced; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000627:therapeutic use; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000601:surgery / Q000628:therapy; D012996:Solutions
chemical_list: D000970:Antineoplastic Agents; D002712:Chlorides; D009944:Organoplatinum Compounds; D012996:Solutions; D000077150:Oxaliplatin
keywords: Carrier solutions; Degradation; Hyperthermic intraperitoneal chemotherapy; Oxaliplatin