A simple procedure for determining the aqueous half-lives of pyrrolic metabolites of pyrrolizidine alkaloids.
We report a simple and rapid procedure for estimating the aqueous half-lives of the reactive metabolites of pyrrolizidine alkaloids that are responsible for toxicity. The metabolites (dehydroalkaloids; DHAs) were rapidly added to a 0.5 mM HEPES solution, pH 8.0. The subsequent fall in pH, due to ester hydrolysis, was followed potentiometrically. The change in pH was well described by single-component exponential decay, allowing the derivation of rate constants and half-lives of hydrolysis. Half-lives varied from 0.31 sec for dehydro-7-acetyllycopsamine to 5.36 sec for dehydrotrichodesmine. The results support the view that alkaloids whose DHA metabolites have longer half-lives produce greater extrahepatic toxicity.
Cooper
R A
RA
Department of Pharmacology, College of Medicine, University of Arizona, Tucson 85724, USA.
Huxtable
R J
RJ
D000818:Animals; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D013329:Structure-Activity Relationship
D011763:Pyrrolizidine Alkaloids