Abstract

In Vitro Circuit Stability of 5-Fluorouracil and Oxaliplatin in Support of Hyperthermic Isolated Hepatic Perfusion

^* Shadyside Hospital Perfusion Services, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
^† Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
^‡ Division of Surgical Oncology, Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
^§ Clinical Research Services, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
^¶ Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
^∥ Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
^# Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania

Address correspondence to: Jan H. Beumer, PharmD, PhD, University of Pittsburgh Cancer Institute Room G27D, Hillman Research Pavilion 5117 Centre Avenue, Pittsburgh, PA 15213-1863. E-mail: beumerjh@upmc.edu

Received: 28 January 2009
Accepted: 13 October 2009

Abstract

Over the years, a large number of drugs have been used in isolated perfusion of extremities or organs. To interpret the pharmacokinetics of these drugs correctly, the contributions of tissue or organ clearance and chemical degradation, respectively, to overall drug elimination from the circuit need to be identified. In support of a phase I clinical trial of isolated hepatic perfusion (IHP), delivering 5-fluorouracil (5-FU) and oxaliplatin to patients with colorectal cancer hepatic metastases, we aimed to characterize the stability of 5-FU and oxaliplatin in the IHP circuit. Stability of 5-FU and oxaliplatin was assessed in human blood, lactated Ringer infusion (LRI), and in an in vitro IHP circuit consisting of both blood and LRI. Samples were analyzed with liquid chromatography tandem mass spectrometry (5-FU) and atomic absorption spectrophotometry (oxaliplatin). 5-FU was stable under all tested in vitro conditions, but ultrafilterable platinum concentrations decreased slowly with a half-life of 85 minutes in both IHP perfusate and whole blood. The stability of 5-FU in the media containing blood is likely attributable to saturation of dihydropyrimidine dehydrogenase. The decrease of ultrafilterable platinum in blood-containing media with an 85 minutes half-life is in agreement with previous reports on oxaliplatin biotransformation. Oxaliplatin and 5-FU are sufficiently stable in the circuit for the 1-hour perfusion in ongoing and planned clinical trials.