Aspirin acetylates the tricyclic antidepressant amoxapine spontaneously to N-acetylamoxapine in vitro and in vivo.
1. N-Acetylamoxapine is formed nonenzymically in vitro, and in mice, from amoxapine, a tricyclic antidepressant, and aspirin. 2. Formation of acetylamoxapine from amoxapine and aspirin in vitro was maximal at pH 5.0 since this pH optimized reactant solubilities as well as decreasing aspirin hydrolysis. 3. Formation of aceylamoxapine from amoxapine and aspirin in mouse stomachs was rapid, and the pH study indicates that the intestinal pH would favour formation even more. 4. Acetylamoxapine administered to mice produced the same CNS-related signs, leading to death, as with amoxapine, but much larger doses and longer time periods were required to elicit these effects. As brain and liver levels of amoxapine in animals dying from acetylamoxapine administration were less than half those found in animals given lethal doses of amoxapine, the toxicity in mice of acetylamoxapine may not be due solely to deacetylation of acetylamoxapine to the parent compound.
Middleberg
R
R
Department of Pharmacology, Thomas Jefferson University, Philadelphia, PA 19107.
Rieders
F
F
Kocsis
J J
JJ
D000107:Acetylation; D000657:Amoxapine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001241:Aspirin / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003989:Dibenzoxazepines / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D015394:Molecular Structure
D003989:Dibenzoxazepines; C060078:N-acetylamoxapine; D001241:Aspirin; D000657:Amoxapine