Comparative Diffusion Study of Two Nitrosoureas: Carmustine and Fotemustine in Normal Rat Brain, Human and Rat Brain Biopsies

Abstract

In order to assess the apparent diffusion coefficient of two nitrosoureas (carmustine and fotemustine) in the brain, a model of planar diffusion was used in the rat brain and in rat and human brain biopsies. Drugs were deposed on the brain surface at a constant concentration for 30 min. At the end of the diffusion time, the concentration gradient was determined with microelectrodes using voltammetry at 5 different depths in the extracellular space of the gray matter (0–304 μm). Voltammetry with micro-electrodes measured quantitatively intact drug in the brain extracellular space (CV 4% for the 2 drugs) in the range studied. The same procedure was used for human and rat brain biopsies which were held in a small cup. The apparent diffusion coefficients in living animals were 0.49 · 10^––⁶ cm² · s^––1 for carmustine and 0.23 · 10^––6 cm² · s^––1 for fotemustine; in human biopsies, they were 0.84 · 10^––6 cm² · s^––1 for carmustine and 0.37 · 10^––6 cm² · s^––1 for fotemustine. Significant differences in the apparent diffusion coefficients of the drugs were accounted for by the fact that the intracellular penetration of fotemustine was better than that of carmustine.

Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study

“…Overall, FEAM conditioning was well tolerated. Mucositis reached G3/G4 severity in only 30% of cases (median duration 7 days, range [4][5][6][7][8][9][10][11][12][13][14], while G2/G3 chemotherapy-induced nausea and vomiting was documented in 47% of patients, without any G4 episodes. Similarly, 17 and 7% of patients experienced G2 and G3 diarrhea, while no G4 events were observed.…”

“…8 The phosphoalanine group makes the drug highly lipophilic, as shown by the octanol/water partition coefficient, which is in the optimal range compared with other nitrosoureas such as BCNU and CCNU. 9,10 This characteristic allows FTM to cross the blood-brain barrier (BBB), as shown by experimental studies in animals. 11,12 In addition, as FTM does not significantly alter glutathione reductase activity, a more favorable pulmonary toxicity profile for this agent can be predicted compared with BCNU.…”

Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation

“…Its elevated lipophilic properties, higher than those of other classical nitrosoureas such as carmustine (BCNU) and lomustine (CCNU), allow the drug to better penetrate through the blood-brain barrier and into malignant cells [5,6]. As single-agent, fotemustine has shown an activity ranging from 15.5% to 26% in recurrent MGs [7-9].…”

An Overview of Fotemustine in High-Grade Gliomas: From Single Agent to Association with Bevacizumab

“…On the other side, the pharmacologic profile of fotemustine can be more beneficial than that of lomustine in the treatment of gliomas. In fact, fotemustine is more lipophilic than lomustine and so can facilitate fotemustine passage through the blood-brain barrier [3]; moreover, fotemustine demonstrated greater diffusion in neuronal cells and glia than lomustine and carmustine [31]. Liver and kidney toxicity due to fotemustine treatment are moderate and less frequent when compared with other drugs belonging to the group of nitrosourea family [5].…”