Excretion of pyrrolic metabolites in the bile of rats given the pyrrolizidine alkaloid retrorsine or the bis-N-ethylcarbamate of synthanecine A.

(1) A comparison has been made in male rats between the biliary excretion of pyrrolic metabolites from the pyrrolizidine alkaloid retrorsine and a synthetic analogue 1-methyl-2,3-pyrroline-bis-N-ethyl-carbamate (Synthanecine A bis-N-ethylcarbamate). (2) When bile duct-cannulated rats were given retrorsine (40 mg/kg) and the bile collected at 1 h intervals, the relative concentration of pyrrolic metabolites was greatest in the first 1 h sample and was negligibly small by 7 h after dosing. By 7 h, about 25% of the dose had been excreted as pyrrolic metabolites. (3) In rats given [3H]synthanecine A bis-N-ethylcarbamate (40 mg/kg), the amounts of radioactivity and the relative levels of pyrrolic metabolites in the bile were greatest in the first 0.5 h sample and became negligibly small by 4 h after dosing. Within this time, about 25% of the dose had been excreted as [3H]radioactivity in the bile only about 5% as pyrrolic metabolites. (4) When rats were given [3H]2,3-bishydroxymethyl-1-methyl pyrrole (10 mg/kg), a proposed pyrrolic metabolite of synthanecine A bis-N-ethylcarbamate, about 17% of the dose was excreted for as [3H]radioactivity in the bile but only about 3% could be accounted for as pyrrolic metabolites. (5) Thin-layer chromatography of bile from rats given [3H]2,3-bishydroxy-methyl-1-methylpyrrole or [3H]synthanecine A bis-N-ethylcarbamate showed little redioactivity or Ehrlich-positive pyrrolic metabolites with an RF value corresponding to that of 2,3-bishydroxymethyl-1-methylpyrrole. A large proportion of the radioactivity label and most of the Ehrlich positive pyrrolic metabolites were associated with highly polar derivatives at the origin of the TLC plate. (6) It was concluded that biliary excretion plays an important role in the disposal of metabolites from both retrorsine and synthanecine A bis-N-ethyl-carbamate though not for the parent compounds. The expected hydroxy-methyl pyrrolic metabolites undergo further modification to more polar derivatives. In the case of retrorsine, these retained their abilities to react with Ehrlich reagent, while with pyrrolic metabolites from synthanecine A bis-N-ethylcarbamate, substatial conversion to Ehrlich negative derivatives occurred. (7) When bile of rats given [3H]synthanecine A bis-N-ethylcarbamate was injected intraduodenally into recipient animals, reabsorbtion of the radioactive label accounted for less than 4% of the dose given to the donor animals, indicating the enterohepatic circulation is probably only of minor importance influencing the elimination of these compounds.