Letter to the editor

Acenocoumarol’s pharmacokinetic: linear or not?

Parveen Kumar1, Puneet Kapoor1, Chhikara Meenu2[*]

1Pharmalex India Pvt Ltd., New Delhi, India

2School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India

EXCLI J 2019;18:Doc679


Dear Editor,

Acenocoumarol, is a racemic mixture of the optical R (+) and S (-) enantiomers. R (+) enantiomer is several times more potent than the S (-) enantiomer (Godbillon et al., 1981[1]). Acenocoumarol is rapidly absorbed following oral absorption with approximately 60 % of the dose available systemically (Trailokya, 2015[13]). After a single dose of 10 mg, the peak plasma concentrations (Cmax) of acenocoumarol are reached within 1-3 h and the area under the plasma concentration-time curve (AUC) values are proportional to the dose in the dosage range of 8 to 16 mg (Sasso et al., 2012[8]). The protein binding of acenocoumarol is 98 % (Trailokya et al., 2016[14]). Acenocoumarol is mainly metabolized by CYP2C9 (Trailokya, 2015[13]); 6- and 7-hydroxylation of both enantiomers of acenocoumarol are the major metabolites (Thijssen et al., 2000[11]). The elimination half-life of acenocoumarol is 8 to 11 h (Sánchez et al., 2013[7]). Approximately, 29 % of acenocoumarol excrete in feces and 60 % in urine. The starting dose of acenocoumarol usually ranged from 2 to 4 mg. Based on the prothrombin time, subsequent loading doses may be recommended (Trailokya, 2015[13]).

Acenocoumarol is reported to exhibit a dose-proportional pharmacokinetics for the 8 to 16 mg doses (Trailokya, 2015[13]). However, no information is available for the dose-proportionality of lower doses of acenocoumarol (i.e. 1 to 4 mg doses). We aimed to evaluate the dose-proportionality of acenocoumarol by performing a literature search and plotting a linear curve for AUC vs. dose from the available information.

Literature related to pharmacokinetics of acenocoumarol was searched in PubMed. A total of 115 from 1618 articles were identified related to acenocoumarol's pharmacokinetics. From, 115 articles, 9 articles were identified as potentially relevant, as these articles reported the AUC values at different time points such as 24, 48, 72 h and at infinite time. These articles were finally considered for the evaluation of linearity of acenocoumarol pharmacokinetics. Various studies have reported the AUC0-48 and AUC0-∞ 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 AUC0-48 and AUC0-∞ were available with the 2, 8 and 16 mg dose. The pharmacokinetics data across these studies were used to generate a dose-proportionality curve (acenocoumarol dose vs. AUC0-48 or acenocoumarol dose vs. AUC0-∞). The dose-proportionality curves between AUC and acenocoumarol doses (AUC0-48 vs. dose, and AUC0-∞ vs. dose) are presented in Figure 1(Fig. 1).

An R2 of 1 indicates that the regression predictions perfectly fit the data. Therefore, from the value of R2 (0.9988 for AUC0-48 vs. dose, and 0.9874 for AUC0-∞ vs. dose), it is clear that acenocoumarol exhibits a dose-proportional pharmacokinetics.



1. Godbillon J, Richard J, Gerardin A, Meinertz T, Kasper W, Jahnnchen. Pharmacokinetics of the enantiomers of acenocoumarol in man. Br J Clin Pharmac. 1981;12:621-9.
2. Huang HL, Vaidyanathan S, Yeh CM, Bizot MN, Dieterich HA, Dole WP, et al. Effect of aliskiren, an oral direct renin inhibitor, on the pharmacokinetics and pharmacodynamics of a single dose of acenocoumarol in healthy volunteers. Curr Med Res Opin. 2008;24:2449-56.
3. Masche UP, Rentsch KM, von Felten A, Meier PJ, Fattinger KE. No clinically relevant effect of lornoxicam intake on acenocoumarol pharmacokinetics and pharmacodynamics. Eur J Clin Pharmacol. 1999;54:865-8.
4. Popovic J, Mikov M, Jakovljevic V. Pharmacokinetic analysis of a new acenocoumarol tablet formulation during a bioequivalence study. Eur J Drug Metab Pharmacokinet. 1994;19:85-9.
5. Public Assessment Report of the Medicines Evaluation Board in the Netherlands (RVG 113318). Acenocoumarol PharmaMatch 1 mg, tablets Pharmamatch B.V., the Netherlands, 2013. Available at: https://db.cbg-meb.nl/Pars/h113318.pdf
6. Rolan P, Terpstra IJ, Clarke C, Mullins F, Visser JN. A placebo-controlled pharmacodynamic and pharmacokinetic interaction study between tamsulosin and acenocoumarol. Br J Clin Pharmacol. 2003;55:314-6.
7. Sánchez M, Escolar G, Reverter JC. Bleeding in patients on anticoagulant therapy: the real utility of antidotes and how to manage bleeding in patients on new-generation oral anticoagulant. Emergencias. 2013;25:482-90.
8. Sasso J, Carmona P, Quiñones L, Ortiz M, Tamayo E, Varela N, et al. Bioequivalence of acenocoumarol in chilean volunteers: an open, randomized, double-blind, single-dose, 2-period, and 2-sequence crossover study for 2 oral formulations. Arzneimittelforschung. 2012;62:395-9.
9. Sunkara G, Bigler H, Wang Y, Smith H, Prasad P, McLeod J, et al. The effect of nateglinide on the pharmacokinetics and pharmacodynamics of acenocoumarol. Curr Med Res Opin. 2004;20:41-8.
10. Thijssen HH, Baars LG. Active metabolites of acenocoumarol: do they contribute to the therapeutic effect? Br J Clin Pharmacol. 1983;16:491-6.
11. Thijssen HH, Flinois JP, Beaune PH. Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes. Drug Metab Dispos. 2000;28:1284-90.
12. Thijssen HH, Hamulyàk K. The interaction of the prostaglandin E derivative rioprostil with oral anticoagulant agents. Clin Pharmacol Ther. 1989;46:110-6.
13. Trailokya A. Acenocoumarol in thromboembolic disorders. Cardiovasc Pharm Open Access. 2015;4 (4):1-4.
14. Trailokya A, Hiremath JS, Sawhney J, Mishra YK, Kanhere V, Srinivasa R, et al. Acenocoumarol: a review of anticoagulant efficacy and safety. J Assoc Physicians India. 2016;64(2):88-93.

Figure 1: Dose-proportionality curves between AUC and acenocoumarol doses (AUC0-48 vs. dose, and AUC0-∞ vs. dose)


Table 1: AUC0-48 and AUC0-∞ values of acenocoumarol from literature search

[*] Corresponding Author:

Chhikara Meenu, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi - 110062, India, eMail: mcchhikara@gmail.com