Renal, biliary and intestinal clearance of a quaternary ammonium compound, emepronium in the dog.

Abstract

Abstract Different routes of elimination of emepronium have been quantitated in conscious and anaesthetized dogs. Smoothed plasma concentration time curves and urinary excretion data obtained following intravenous bolus injection of 5 mg/kg indicate at least four different phases with the following half‐lives: 5 min., I hour, 10 hours and 9 days. The initial dilution space, 0.2‐0.6 l/kg, is rather similar to the extracellular volume (0.20‐0.35 l/kg). From infusion experiments plasma clearance of emepronium have been found to be 33±2 ml. min‐1.kg‐1 (meani ± S.E.M., n = 14). The drug is secreted by the renal tubules at a maximum rate of 20 μg/min. at a plasma concentration of about 200 μg/l. Compared with other quaternary ammonium compounds, this is an easily saturated mechanism with a low capacity. The renal clearance constitutes about 30 % of the plasma clearance at a plasma concentration of 200 μg/l. The biliary excretion rate increases proportionally to a plasma concentration up to 100 μg/l and then reaches a maximal rate which is dependent on the bile flow. The biliary clearance decreases from 7 to 2 ml.min.‐1.kg‐1 when the bile flow changes from 7 to 4 g/ hour and the plasma concentration is 200 μg/l. Experiments with bile diversion and saline perfusion of isolated intestinal segments reveal an intestinal route of elimination of both emepronium and metabolites. The bile diversion experiments indicate that about 5‐15% of an intravenous dose is excreted through the gastrointestinal epithelium. Perfusion of isolated intestinal loops indicates an apparent clearance of 4‐5 ml. min‐1.m‐1 over a wide range of steady state plasma concentrations (20‐1200 μ/l). An apparent total intestinal clearance could be calculated to about 7 ml. min.‐1.kg‐1. The remaining part of the plasma clearance (about 8 ml. min.‐1. kg‐1 in an anaesthetized dog) is accounted for by metabolism. The degree of protein binding has been shown to be low, about 20 per cent, and the red blood cell penetration in vitro is only 1‐10% of the total amount present in whole blood.