Pharmacokinetics of fluorinated 2-nitroimidazole hypoxic cell radiosensitizers in murine peripheral nervous tissue.
We have previously reported that KU-2285, a 2-nitroimidazole with a fluorinated N1-substituent (-CH2-CF2CONH(CH2)nOH, n = 2), was a promising hypoxic cell radiosensitizer. In this study the pharmacokinetics of KU-2285 and its related compounds (n = 3 and n = 4) were compared with those of etanidazole (a 2-nitroimidazole with an N1-substituent of -CH2CONH(CH2)nOH, n = 2) and its related compounds (n = 3 and n = 4) to assess the effects of incorporation of a CF2 group. The lipophilicity of the fluorinated compounds was higher than that of etanidazole, as measured by the octanol/water partition coefficient. As the number of CH2 groups increased, the lipophilicity of the compounds in both the KU-2285 and etanidazole series increased. The brain tissue levels of the fluorinated compounds were as low as those of the etanidazole derivatives, while the biological half-lives of the fluorinated compounds in peripheral nervous tissues were shorter than those of related non-fluorinated compounds.
Sasai
K
K
Department of Radiology, Faculty of Medicine, Kyoto University, Japan.
Iwai
H
H
Yoshizawa
T
T
Nishimoto
S
S
Shibamoto
Y
Y
Kitakabu
Y
Y
Oya
N
N
Takahashi
M
M
Abe
M
M
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D017341:Etanidazole; D005260:Female; D006207:Half-Life; D051379:Mice; D008809:Mice, Inbred C3H; D009593:Nitroimidazoles / Q000378:metabolism / Q000493:pharmacokinetics*; D010525:Peripheral Nerves / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics*
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; C069296:KU 2285; D017341:Etanidazole