RT Journal Article
SR Electronic
T1 Biliary excretion of pyrrolic metabolites of [14C]monocrotaline in the rat.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 422
OP 429
VO 23
IS 3
A1 Lamé, M W
A1 Jones, A D
A1 Morin, D
A1 Segall, H J
A1 Wilson, D W
YR 1995
UL http://dmd.aspetjournals.org/content/23/3/422.abstract
AB The biliary excretion of amphoteric pyrroles was studied using in situ isolated rat liver preparations perfused in a recirculatory manner for 60 to 90 min with 14C-monocrotaline (40 mumol/120 ml of Krebs-Henseleit buffer). After 90 min, 20% of the administered 14C and an amount of pyrrole equivalent to 9 mumol of dehydroretronecine was recovered in the bile. Bile collected between 15 and 30 min contained the highest levels of 14C and pyrrolic metabolites. Isoelectric focusing (IEF) and electrophoretic separations on matrices of polyacrylamide and silica were used to isolate and estimate levels of pyrrolic conjugates. IEF and electrophoretic separations on silica revealed the presence of six pyrrole-positive metabolites. Reactions of monocrotaline pyrrole with glutathione produced three conjugates that had the same pI values as components found in bile. Electrophoretic separations on silica and polyacrylamide followed by reversed phase chromatography removed sufficient biliary matrix contaminants to permit identification of glutathione and cysteinyl-glycine conjugates of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine and 1-formyl-7-hydroxy-6,7-dihydro-5H-pyrrolizine with fast atom bombardment MS/MS. This study revealed a complexity in the biliary pyrrolic excretion profile that had not previously been realized.