Pharmacokinetics of WR-1065 in mouse tissue following treatment with WR-2721.
Levels of reduced glutathione (GSH) and N-(2-mercaptoethyl)-1,3-diaminopropane (WR-1065) were measured in tissues of Balb/c mouse bearing EMT6 tumors at time intervals ranging from 5 min to 48 hr after i.v. injection of S-2-(3-aminopropylamino)ethyl phosphorothioate (WR-2721) at 500 mg per kg. In all tissues examined (liver, kidney, lung, heart, muscle, brain, tumor, spleen, and salivary gland), maximal WR-1065 levels occurred 5-15 min after injection, with levels in liver, kidney, lung, and salivary gland exceeding one mumole per gm. The post-maximum decline in WR-1065 varied markedly with tissue, lung exhibiting a 6-fold drop by 30 min and salivary gland falling only 15% after 3 hr. In a mouse treated with carbon-14 labeled WR-2721 it was found after 15 min that WR-1065 accounted for over half of the total drug in all tissues except tumor, where it accounted for a third of the total drug. There was no evidence that GSH levels were substantially altered by WR-2721 treatment. The results provide the first direct evidence supporting the widely held view that WR-2721 treatment results in intracellular WR-1065 and they demonstrate that high levels of WR-1065 occur very soon after i.v. injection.
D004999:Amifostine / Q000378:metabolism*; D000818:Animals; D008297:Male; D008624:Mercaptoethylamines / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000378:metabolism*; D011837:Radiation-Protective Agents / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
D008624:Mercaptoethylamines; D009946:Organothiophosphorus Compounds; D011837:Radiation-Protective Agents; C020174:N-(2-mercaptoethyl)-1,3-diaminopropane; D004999:Amifostine