Assessment of enterohepatic circulation of radioactivity following a single dose of [14C]nimodipine in the rat.

Abstract

4 male Sprague-Dawley rats with bile-duct fistulae were joined in a cascade. The first animal was given 5 mg/kg of [14C]-labelled nimodipine administered intraduodenally as a bolus. The bile of animals 1 and 2 was dynamically infused intraduodenally respectively into animals 2 and 3 and the bile of animal 3 was collected in fractions and infused i.d. into animal 4. The excretion and the course of the plasma concentration were studied radiometrically. The described investigation technique allows a detailed determination of the quantity and the kinetics of reabsorption and excretion during each observed pass of radioactivity in the enterohepatic circulation. On the basis of the balance between radioactivity administered and recovered and of the course of the plasma concentration it has been shown, on the example of nimodipine, that the experiment successfully simulates the situation in the intact animal. The [14C]Nimodipine radioactivity is subject to pronounced enterohepatic circulation: on average 43% of the amount excreted with the bile is reabsorbed with each recirculation and 57% is excreted with the faeces, 81% and 19% of the quantity reabsorbed being excreted respectively with the bile and urine. Because of the repeated reabsorption, the effective dose is increased by 54% and the drop in plasma concentration is slowed down in the middle time interval between 3 and 15 h after administration. The kinetic processes (absorption, excretion) become slower with each recirculation. An increasing fraction of the absorbed radioactivity undergoes direct hepatic excretion, by-passing the systemic circulation.