Pharmacokinetics of 2-nitroimidazole hypoxic cell radiosensitizers in rodent peripheral nervous tissue.
The concentrations of seven 2-nitroimidazoles--including misonidazole, etanidazole (SR-2508), pimonidazole (Ro 03-8799), desmethylmisonidazole (Ro 05-9963), RK28, RP170, and KU2285--were measured in the sciatic nerves of C3H/He mice using reverse-phase high-performance liquid chromatography. Drug exposure to the peripheral nervous system was highest for misonidazole, followed by desmethylmisonidazole, etanidazole, pimonidazole and RK28. The lower drug exposure of pimonidazole and RK28 seemed to be related to their lower hydrophilicity. The apparent biological half-lives of the compounds in the peripheral nerves were correlated to their hydrophilicity: the more hydrophilic the compound, the longer the apparent biological half-life in the peripheral nervous tissue of the mice. Measurement of drug exposure in the rodent peripheral nervous system, rather than in the brain, was a better indicator for estimating the occurrence of clinical peripheral neuropathy by 2-nitroimidazoles.
Sasai
K
K
Department of Radiology, Faculty of Medicine, Kyoto University, Japan.
Shibamoto
Y
Y
Takahashi
M
M
Ito
T
T
Nishimoto
S
S
Abe
M
M
D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D009593:Nitroimidazoles / Q000493:pharmacokinetics*; D010525:Peripheral Nerves / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents