Pharmacokinetics of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] in human patients: Implications for hypoxia measurements in vivo by 2-nitroimidazoles

Objectives: Pharmacokinetic studies were performed on the first 28 patients enrolled in a phase I trial to determine the ability of EF5 [2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] to detect hypoxia in human tumors in the absence of patient toxicity. Methods: EF5 was made in purified form and formulated for intravenous injection by the National Cancer Institute. After obtaining consent from the patients, EF5 was administered and blood samples were drawn at various times over approximately 48 h. For most patients it was possible to collect total urine at approximately 8-h intervals. EF5 in plasma and urine was analyzed by high-performance liquid chromatography. Results: EF5's plasma concentration followed a simple exponential decay following infusion. The plasma half-life was 11.7 ± 2.6 h (± SD) and was not affected by drug dose (9 to 28 mg/kg), fractional urine recovery, patient weight or gender. Absolute plasma values suggested even biodistribution of the drug throughout the soft tissue with a volume of distribution equal to 0.56 l/kg. Despite the relatively high lipid partition coefficient (logP = 0.6), EF5 was excreted primarily (up to 70%) via kidney clearance. No drug metabolites (e.g. retaining the 2-nitroimidazole chromophore) were detected in either plasma or urine. No toxicity was found at drug doses adequate to detect tumor hypoxia. Conclusions: Currently held paradigms of 2-nitroimidazole metabolism (e.g. clearance rate and toxicity as affected by octanol/water partition coefficient) are discussed. The results reported herein suggest that EF5 is biologically stable with predictable pharmacokinetics. EF5's consistent half-life and clearance properties will allow quantitative analysis of EF5 binding relative to tissue oxygen levels.