TY - JOUR
T1 - The development of an oral prodrug, SR-2545, of the 2-nitroimidazole radiosensitizer SR-2508
AU - Coleman, C. Norman
AU - Lee, William W.
AU - Constine, Louis S.
AU - Brown, J. Martin
N1 - Funding Information:
Reprint requests to: C. Norman Coleman, M.D. This work was supportsd by Research Grant CA-15201 and Research Contract CM-87207, both from the National Cancer Institute, DHHS.
PY - 1982
Y1 - 1982
N2 - 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 elimination. 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 radiosensitization. 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.
AB - 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 elimination. 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 radiosensitization. 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.
KW - Pharmacology
KW - Radiosensitizers
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U2 - 10.1016/0360-3016(82)90654-X
DO - 10.1016/0360-3016(82)90654-X
M3 - Article
C2 - 6213588
AN - SCOPUS:0019988958
SN - 0360-3016
VL - 8
SP - 431
EP - 434
JO - International journal of radiation oncology, biology, physics
JF - International journal of radiation oncology, biology, physics
IS - 3-4
ER -