Pharmacokinetic studies of amino acid analogues of 2-nitroimidazole, new hypoxic cell radiosensitizers
A series of new analogues of 2-nitroimidazole has been synthesized by inserting various amino acids at 1-position through an amide bond. The ethyl esters were found to be the most effective radiosensitizers in vitro against hypoxic Chinese hamster (V-79) cells. However, the free acid of phenylalanine analogue was less active as a radiosensitizer and required 5 mM concentration to produce SER of 1.9. In contrast, the free acid of tyrosine analogue was inactive in this test system. The pharmacokinetic studies with the esters revealed their rapid hydrolysis in serum to the corresponding acids within 5 minutes as detected by HPLC. The pharmacokinetic parameters were therefore determined by employing the free acid analogues and solubilizing them as their sodium salts. The drugs were administered intraperitoneally at 0.5 mg/g dose level to C-57 mice bearing B16 melanoma. Peak tumor concentration of approximately 217 ug/g was achieved within 15 min with phenylalanine analogue. The tumor to brain ratio was 10:1 suggesting that this agent is excluded from CNS and that the phenylalanine analogue should be considered a potentially less neurotoxic radiosensitizer than misonidazole.
- Research Organization:
- Tulane Univ. School of Medicine, New Orleans, LA
- OSTI ID:
- 6500656
- Journal Information:
- Int. J. Radiat. Oncol., Biol. Phys.; (United States), Journal Name: Int. J. Radiat. Oncol., Biol. Phys.; (United States) Vol. 10:8; ISSN IOBPD
- Country of Publication:
- United States
- Language:
- English
Similar Records
Fluorinated 2-nitroimidazole derivative hypoxic cell radiosensitizers: Radiosensitizing activities and pharmacokinetics
The pharmacokinetics in mice and dogs of nitroimidazole radiosensitizers and chemosensitizers more lipophilic than misonidazole
Related Subjects
560121* -- Radiation Effects on Cells-- External Source-- (-1987)
560152 -- Radiation Effects on Animals-- Animals
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AMINO ACIDS
ANIMAL CELLS
ANIMALS
ANOXIA
AZOLES
CARBOXYLIC ACIDS
CELL KILLING
CONNECTIVE TISSUE CELLS
DISEASES
ELECTROMAGNETIC RADIATION
ESTERS
FIBROBLASTS
HAMSTERS
HETEROCYCLIC COMPOUNDS
HYDROXY ACIDS
IMIDAZOLES
IONIZING RADIATIONS
MAMMALS
MELANOMAS
MICE
NEOPLASMS
NITRO COMPOUNDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHARMACOLOGY
PHENYLALANINE
RADIATIONS
RADIOINDUCTION
RADIOSENSITIVITY EFFECTS
RODENTS
SOMATIC CELLS
TYROSINE
VERTEBRATES
X RADIATION