Subcutaneous administration of amifostine (ethyol) is equivalent to intravenous administration in a rat mucositis model.
OBJECTIVE
Amifostine (Ethyol) is currently approved for intravenous (IV) administration to prevent xerostomia in patients receiving radiotherapy for head-and-neck cancer. Recently, subcutaneous (SC) administration has been explored as an alternative route. To determine whether SC administration was equivalent to IV administration, we used models to follow pharmacokinetics and oral mucosal protection in rats.


METHODS
Amifostine was administered to rats at doses of 200, 100, or 50 mg/kg (1300, 650, or 325 mg/m(2)) IV or SC at various times before radiation at 15.3 Gy (protection studies) or harvest of blood and tissues for analysis by HPLC (pharmacokinetic studies).


RESULTS
Amifostine administered IV or SC 1 h before radiation protected rats from mucositis, but the protective effect was more prolonged when amifostine was administered SC. Tissue levels of the active metabolite (WR-1065) were equivalent after SC administration. The correlation between tissue levels of WR-1065 and protection was strong, but that between blood levels of WR-1065 and protection was only weak.


CONCLUSIONS
These data demonstrate that, in a rat model, SC administration of amifostine was at least as effective as that by IV.
Cassatt
David R
DR
Department of Molecular Biology/Biochemistry, MedImmune, Inc., Gaithersburg, MD 20872, USA. cassatt@medimmune.com
Fazenbaker
Christine A
CA
Kifle
Gizachew
G
Bachy
Christine M
CM
D004999:Amifostine / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D005260:Female; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008624:Mercaptoethylamines / Q000378:metabolism; D023421:Models, Animal; D009061:Mouth Mucosa / Q000187:drug effects / Q000528:radiation effects; D011832:Radiation Injuries / Q000378:metabolism / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013280:Stomatitis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D014987:Xerostomia
D008624:Mercaptoethylamines; D011837:Radiation-Protective Agents; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004999:Amifostine