Pharmacokinetics and tumor and neural tissue penetrating properties of SR-2508 and SR-2555 in the dog-hydrophilic radiosensitizers potentially less toxic than misonidazole
- Dept. of Clinical Veterinary Medicine, Cambridge, England
The behavior of three 2-nitroimidazole drugs of similar electron affinity to misonidazole but with varying octanol: water partition coefficients has been compared in normal and tumor-bearing dogs. In particular the pharmacokinetic behavior, urinary excretion, and tumor and neural tissue penetrating properties of the three drugs have been studied. Peak plasma concentrations and plasma clearance rates increased with decreasing lipophilicity. Penetration into both the central and peripheral nervous system was significantly slower for the more polar drugs, and as a result of this and the increased plasma clearance rates, the drug exposure to these sites of potential neurotoxicity was reduced. Peak tumor concentrations increased with decreasing lipophilicity, and those for the two SR drugs were more than twice those for equimolar iv doses of misonidazole. It would seem on the basis of the increased plasma clearance rates, improved peak tumor concentrations, and reduced drug exposure to neural tissue that lowering lipophilicity may be an important means of designing radiosensitizing drugs which are less toxic than and superior to misonidazole.
- OSTI ID:
- 6673576
- Journal Information:
- Radiat. Res.; (United States), Journal Name: Radiat. Res.; (United States) Vol. 84:3; ISSN RAREA
- Country of Publication:
- United States
- Language:
- English
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63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
ANTINEOPLASTIC DRUGS
AZOLES
BIOLOGICAL MATERIALS
BIOLOGICAL WASTES
BLOOD-PLASMA CLEARANCE
BODY FLUIDS
CEREBROSPINAL FLUID
CLEARANCE
COMPARATIVE EVALUATIONS
CORRELATIONS
DISEASES
DOGS
DRUGS
EXCRETION
HETEROCYCLIC COMPOUNDS
IMIDAZOLES
LIPIDS
MAMMALS
MATERIALS
MISONIDAZOLE
NEOPLASMS
NERVOUS SYSTEM
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHARMACOLOGY
POLAR COMPOUNDS
UPTAKE
URINE
VERTEBRATES
WASTES