Passage of 5'-dFUrd and its metabolites 5-FU and 5-FUH₂to CSF in a clinical Phase 1 study

Abstract

Lumbar puncture was performed on eight patients in a clinical Phase 1 study of doxifluridine (5'-dFDrd). 5'-dFUrd, 5'FU, and 5-FUH2 were shown to cross the blood-brain barrier to CSF. The maximal concentrations of 5'-dFUrd and 5-FUH2 were about 1-3% of the maximal concentrations in plasma, and were reached within 1-4 h after the end of iv infusion of 5'-dFUrd. 5-FUH2 showed a marked increase in CSF between 3 and 4 h to about 40-60% of the maximal plasma concentration in 5 of the patients, indicating a possible further increase after 4 h. The relationship between the concentrations of 5'-dFUrd and its metabolites in the CSF, and CNS toxicity is discussed.

Are Capecitabine and the Active Metabolite 5-FU CNS Penetrable to Treat Breast Cancer Brain Metastasis?

“…Combining the in vitro unbound fraction in blood and brain homogenate, both K p,uu,brain and K p,uu,CSF were calculated to be 0.03 and 0.25 for capecitabine and 0.13 and 0.29 for 5-FU, respectively ( Table 2). The brain penetration of 5-FU in our study was comparable to the studies conducted by Bourke et al (1973) (K p,brain = 0.09 and K p,CSF = 0.43 in primates after IV injection of 5-FU-2-14 C), Kerr et al (1984) (K p,CSF = 0.11-0.48 in monkey after IV injection of 5-FU), and Heier et al (1986) (K p,CSF = 0.015-0.06 in human after IV injection of 59-DFUR). These data suggested that capecitabine and 5-FU had very poor brain penetration and low CSF penetration.…”

No adverse effects of adjuvant chemotherapy on hippocampal volumein Japanese breast cancer survivors

“…Several studies have demonstrated subtle hippocampal damage to often give rise to explicit memory deficits [5][6][7][8][9]. Chemotherapeutic agent such as fluorouracil which is commonly used for breast cancer, penetrate the blood brain barrier [10] and may inhibit neurogenesis in the hippocampus. We hypothesized that adjuvant chemotherapy might damage the hippocampus and result in memory impairment.…”

Capecitabine-associated cerebellar ataxia

“…Both of these metabolites were shown to cross the blood-brain barrier in a Phase I study. 23 Since the 5′-DFUR molecule consists of a pentose sugar attached to fluorouracil, 5′-DFUR crosses the blood-brain barrier more easily than fluorouracil itself. 24 Capecitabine may cross the blood-brain barrier via the human concentrative nucleoside transporter in the form of 5′-DFUR, which was converted to fluorouracil due to the high concentration of thymidine phosphorylase in brain cells.…”