Acenocoumarol and its amino and acetamido metabolites. Comparative pharmacokinetics and pharmacodynamics in the rat

Abstract

Abstract The elimination, distribution and anticoagulant activity of racemic acenocoumarol, its amino (AM) and acetamido (AA) derivative were determined in male Wistar rats after subcutaneous injection of a single dose of 2 mg kg−1. The effect of daily administration of acenocoumarol on the prothrombin complex activity (PCA) was also investigated. A rapid onset of the hypothrombogenic effect was observed for all three derivatives with the half-life of decline of PCA=3˙6 h. The duration of the hypothrombogenic effect was short for the drug and its AA derivative and long for the AM compound (normalization at about 24 and 70 h, respectively), parallelling the half-life of elimination of the compounds of, 3˙3, 4, and 8 h respectively. Daily administration of acenocoumarol for 8 days showed no change in the kinetics of the anticoagulant effect. Elimination of the drug is solely by metabolism. Reduction of the 4′-nitro group was not a metabolic route of importance; the amount of its two derivatives cumulatively excreted in urine over 5 days accounted for 2–3% of the dose only. Elimination of AM derivative is mainly by acetylation to AA, the compound which itself is eliminated by renal excretion. The distribution of acenocoumarol between liver and plasma was determined. The liver to plasma ratio was higher than 1 beyond 10 min after administration. The elimination rate of the drug from liver was slower than from plasma giving an increase in liver to plasma ratio in time. Plasma protein binding was extensive, being the highest for the drug; 1˙81, 2˙84 and 3˙89% free for drug, AM, and AA derivative, respectively.