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The development of an oral prodrug, SR-2545, of the 2-nitroimidazole radiosensitizer SR-2508

Journal Article · · Int. J. Radiat. Oncol., Biol. Phys.; (United States)
 [1]; ; ;
  1. Stanford Univ., CA
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SR-2508, a 2-nitroimidazole radiosensitizer, is expected to be clinically superior to desmethylmisonidazole or misonidazole because of its lower lipophilicity with subsequent lower drug levels in neural tissue and more rapid plasma eliminaton. The intravenous route of administration will be optimal but oral drugs may be necessary. Since decreased lipophilicity will decrease oral absorption we have synthesized, and tested in mice, SR-2545, an acetate ester prodrug of SR-2508. In the liver there is complete first pass metabolism to parent drug with no prodrug detectable in the blood. Compared to an equal dose of oral SR-2508, the prodrug yields a more rapid, reproducible, plasma peak with twice the bioavailability, peak plasma concentration and radiosensitizaton. If oral preparations of SR-2508 are to be used in the clinic the prodrug, SR-2545, is likely to be superior to oral SR-2508.

OSTI ID:
6718779
Journal Information:
Int. J. Radiat. Oncol., Biol. Phys.; (United States), Journal Name: Int. J. Radiat. Oncol., Biol. Phys.; (United States) Vol. 8:3/4; ISSN IOBPD
Country of Publication:
United States
Language:
English

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Related Subjects

550500* -- Metabolism
550603 -- Medicine-- External Radiation in Therapy-- (1980-)
560305 -- Chemicals Metabolism & Toxicology-- Vertebrates-- (-1987)
59 BASIC BIOLOGICAL SCIENCES
62 RADIOLOGY AND NUCLEAR MEDICINE
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMALS
AZOLES
BODY
CARBOXYLIC ACID ESTERS
DIGESTIVE SYSTEM
DRUGS
ESTERS
GLANDS
HETEROCYCLIC COMPOUNDS
IMIDAZOLES
LIVER
MAMMALS
METABOLISM
MICE
NERVOUS SYSTEM
NITRO COMPOUNDS
ORAL ADMINISTRATION
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PHARMACOLOGY
RADIOSENSITIZERS
RODENTS
VERTEBRATES