Evaluation of the enterohepatic circulation after 3 H-digoxin administration in the rat.

Abstract

After intraduodenal administration of 3H-digoxin (d) in biliary fistula (b.f.) rats, the total radioactivity in blood and bile is eliminated with t1/2 of 7 h in both fluids. In rats with intact enterohepatic circulation (e.c.), a t1/2 of 13.5 h was observed in blood and of 22 h in bile. To explain the much longer t1/2 in bile than in blood, the pharmacokinetics were studied of all substances, which might participate in e.c. after d administration. E.c. of the water soluble fraction is negligible since almost no absorption was found. Digoxigenin-bis- (b) and monodigitoxoside (m) showed approximately the same absorption kinetics as d. However, the blood levels of radioactivity after i.d. administration of these metabolites in b.f. rats were 5–6 times lower than those after d as a consequence of higher biliary excretion. 90–95% of the absorbed amounts of b and m were extrected in bile within 11 h compared with 61% after d administration. Thus the far longer t1/2 of elimination of radioactivity in bile than in blood after i.d. administration of d in rats with e.c. seemed to be due to a short circuit of b and m between intestine and liver. Evidence for this comes from the chromatographic analysis of the total radioactivity in the bile of these animals which shows that significantly more b is present in the bile of rats with e.c. than b.f. rats. No differences were found in the case of m, which on one hand is formed to a lesser extent and is on the other rapidly converted to polar metabolites, which are not reabsorbed.