Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?

Abstract

1 The pharmacokinetics and pharmacodynamics of racemic acenocoumarol (AC), the amino (AM) and acetamido (AA) derivative were investigated in healthy volunteers after administration of a single oral (10 mg) dose. 2 All three coumarins were rapidly absorbed from the gastrointestinal tract. The elimination half-lives were 10.9, 10.4, and 4.1 h, for AC, AM and AA, respectively. 3 After the oral administration of AC, no AM and AA was detected in the plasma, and less than 1% of the dose was recovered in the urine (0-24 h) as AM. 4 Renal clearance was the main route of elimination of AM and AA; the former by glomerular filtration, the latter by active excretion. 5 Binding to serum proteins was the highest for AC (1.52% free). AM and AA were less tightly bound (about 3% free). AM or AA did not interfere with the AC plasma protein binding. 6 The oral administration of AC resulted in a rise in prothrombin time with a maximum effect at 24 to 30 h. No anticoagulant activity was observed upon the administration of AM and AA. 7 The results indicate that the compounds AM and AA, if they are formed out of AC at all, do not contribute to the anticoagulant activity of AC.

4-Hydroxycoumarin Oral Anticoagulants : Pharmacokinetics-Response Relationship

“…Whereas their mechanism of action is similar, i. e. they suppress the vitamin K dependent carboxylation of glutamic acid residues in coagulating factor precursor proteins (2), their pharmacokinetics differ highly. The biological half-life of phenprocoumon (3-5 days) (3,4) is much longer than that of warfarin (t,,, _ 30-80 h) (4), that of acenocoumarol is much shorter (ty, about 10 h) (5). These characteristics are reflected in the time needed for the blood clotting activity (for instance prothrombin time) to recover after cessation of drug administration: about 2 days for acenocoumarol, 3-5 days for warfarin, and 8-15 days for phenprocoumon (6).…”

Pharmacokinetic analysis of a new acenocoumarol tablet formulation during a bioequivalence study

“…[1][2][3]. It is important to determine the individual variations in pharmacokinetics in healthy volunteers (16).…”

“…The above mentioned model was considered adequate for the examination of systemic availability and the first-pass elimination of acenocoumarol, because the drug corresponds to the assumptions of the model (2)(3)(4). It was therefore of practical importance.…”

“…The drug is extensively metabolised in man (2)(3)(4). Reduction of the aromatic nitro-group yields the amino-metabolite, a portion of which is transformed to the N-acetyl-derivative.…”

Acenocoumarol’s pharmacokinetic: linear or not?

“…Various studies have reported the AUC 0-48 and AUC 0-∞ values of acenocoumarol for 1, 4, 10 and 12 mg dose (Table 1(Tab. 1); References in Table 1: Huang et al, 2008[2]; Masche et al, 1999[3]; Popovic et al, 1994[4]; Rolan et al, 2003[6]; Sasso et al, 2012[8]; Sunkara et al, 2004[9]; Thijssen and Baars, 1983[10]; Thijssen and Hamulyàk, 1989[12]). No other information on AUC 0-48 and AUC 0-∞ were available with the 2, 8 and 16 mg dose.…”