Summary
The kinetics and dynamics of single doses (5 mg p.o.) of the optical isomers of acenocoumarol (R-AC and S-AC) were followed in healthy subjects and the effect on them of cimetidine 800 mg/day was also investigated. The AC enantiomers differed greatly in their pharmacokinetics. The mean residence time (MRT) of R-AC was about 10 times longer than that of S-AC, 15 h vs 1.2 h. There was no difference in the volume of distribution. Depression of blood clotting activity (Thrombotest) was observed only after administration of R-AC. The inactivity of S-AC as a vitamin K antagonist must be ascribed to its short MRT. Cimetidine did not affect the acute oral kinetics of R- and S-AC, nor did it affect the anticlotting activity of R-AC. The urinary excretion pattern of the 6- and 7-hydroxylated AC metabolites was not altered during cimetidine treatment. Although the present studies showed no effect of cimetidine on the pharmacokinetics and dynamics of acenocoumarol, the findings of Serlin et al. [3] suggest that cimetidine should not be administered during acenocoumarol therapy.
Similar content being viewed by others
References
Somogyi A, Gugler R (1982) Drug interactions with cimetidine. Clin Pharmacokinet 7: 23–41
Klotz U, Reimann IW (1984) Drug interactions through binding to cytochrome P450: the experience with H2-receptor blocking agents. Pharmacol Res 2: 59–62
Serlin MJ, Sibeon RG, Mossman S, Breckenridge AM, Williams JRB, Atwood JL, Willoughby JMT (1979) Cimetidine: Interaction with oral anticoagulants in man. Lancet 2: 317–319
Desmond PV, Mashford ML, Harman PJ, Morphett BJ, Berween KJ, Wang YM (1984) Decreased oral warfarin clearance after ranitidine and cimetidine. Clin Pharmacol Ther 35: 338–341
O'Reilly A (1984) Comparative interaction of cimetidine and ranitidine with racemic warfarin in man. Arch Int Med 144: 989–991
Kelly JG, O'Mally K (1979) Clinical pharmacokinetics of oral anticoagulants. Clin Pharmacokinet 4: 1–15
Meinertz T, Kasper W, Kahl C, Jähnchen E (1978) Anticoagulant activity of the enantiomers of acenocoumarol. Br J Clin Pharmacol 5: 187–188
Godbillon J, Richard J, Gerardin H, Meinertz T, Kasper W, Jähnchen E (1981) Pharmacokinetics of the enantiomers of acenocoumarol in man. Br J Clin Pharmacol 12: 621–629
Thijssen HHW, Baars LGM, Drittij-Reijnders MJ (1985) Stereoselective aspects in the pharmacokinetics and pharmacodynamics of acenocoumarol and its amino and acetamido derivatives in the rat. Drug Metab Dispos 13: 593–597
Yamaoka K, Nakagawa T, Uono T (1978) Statistical moments in pharmacokinetics. J Pharmacokinet Biopharmacol 6: 547–558
Benet LZ (1979) Noncompartmental determination of the steady-state volume of distribution. J Pharm Sci 68: 1071–1074
Dieterle W, Faigle JW, Sulc M, Theobald W (1977) Biotransformation and pharmacokinetics of acenocoumarol (Sintrom). Eur J Clin Pharmacol 11: 367–375
Thijssen HHW, Baars LG (1983) Active metabolites of acenocoumarol: Do they contribute to the therapeutic effect? Br J Clin Pharmacol 16: 491–496
Banfield C, O'Reilly R, Chan E, Rowland M (1983) Phenylbutazone-warfarin interaction in man: further stereochemical and metabolic considerations. Br J Clin Pharmacol 16: 669–675
Feeley J, Pereira L, Guy E, Hockings N (1984) Factors affecting the response to inhibition of drug metabolism by cimetidine-dose response and sensitivity of elderly and induced subjects. Br J Clin Pharmacol 17: 77–81
Harenberg J, Staiger Ch, Vries JX de, Walter E, Weber E, Zimmermann R (1982) Cimetidine does not increase the anticoagulant effect of phenprocoumon. Br J Clin Pharmacol 14: 292–293
Toon S, Heimark LD, Trager WF, O'Reilly RA (1985) Metabolic fate of phenprocoumon in humans. J Pharm Sci 74: 1037–1040
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Thijssen, H.H.W., Janssen, G.M.J. & Baars, L.G.M. Lack of effect of cimetidine on pharmacodynamics and kinetics of single oral doses of R- and S-acenocoumarol. Eur J Clin Pharmacol 30, 619–623 (1986). https://doi.org/10.1007/BF00542424
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00542424