Summary
Stereochemical aspects of the potential interaction between the oral anticoagulant warfarin and the H2-antagonists, cimetidine and ranitidine, were investigated. A single 25 mg oral dose of racemic warfarin was administered on Day 4 of a randomised 9-day multiple dosing regimen of either cimetidine (800 mg o.d.) ranitidine (300 mg o.d.) or placebo. The degree of anticoagulation produced by warfarin was quantificated by the determination of both the prothrombin and Factor VII clotting times. Ranitidine had no effect on the pharmacodynamics of warfarin or the pharmacokinetics of the individual warfarin enantiomers. Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantiomer, possibly due to metabolic inhibition of this species.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Banfield CR, O'Reilly RA, Chan E, Rowland M (1983) Phenylbutazone-warfarin interaction in man. Further stereochemical and metabolic considerations. Br J Clin Pharmacol 16: 669–675
Banfield CR, Rowland M (1984) Stereospecific fluorescence high-performance liquid chromatographic analysis of warfarin and its metabolites in plasma and urine. J Pharm Sci 73: 1392–1396
Bauman JH, Kimelbatt BJ (1982) Cimetidine as an inhibitor of drug metabolism. Therapeutic implications and review of the literature. Drug Intell Clin Pharm 16: 380–386
Bell JA, Gower AJ, Martin LE, Mills ENC, Smith WP (1981) Interaction of H2-receptor antagonists with drug-metabolising enzymes. Biochem Soc Trans 9: 113–114
Breckenridge AM, Challiner M, Mossman S, Park BK, Serlin MJ, Sibeon RJ, Williams JRB, Willoughy JMT (1979) Cimetidine increases the action of warfarin in man. Br J Clin Pharmacol 8: 392P-393P
Breen KJ, Bury R, Desmond PV, Mashford ML, Morphett B, Westwood B, Shaw RG (1982) Effects of cimetidine and ranitidine on hepatic drug metabolism. Clin Pharmacol Ther 31: 297–300
Choonara AA, Cholerton S, Haynes BP, Breckenridge AM, Park BK (1985) Interaction between the R-enantiomer of warfarin and cimetidine. Br J Clin Pharmacol 21: 85P
Desmond PV, Breen KJ, Harman PJ, Mashford ML, Morphett BJ (1984) Decreased clearance of warfarin after treatment with cimetidine or ranitidine. Clin Pharmacol Ther 35: 338–341
Devanesen S (1981) Prolongation of prothrombin time with cimetidine. Med J Aust 1: 537
Eble JM, West BD, Link KP (1966) A comparison of the isomers of warfarin. Biochem Pharmacol 15: 1003–1006
Freston JW (1982) Cimetidine II. Adverse reactions and patterns of use. Ann Intern Med 97: 728–734
Hertzel D, Birkett D, Miners J (1979) Cimetidine interaction with warfarin. Lancet 2: 639
Hewick DS, McEwan J (1973) Plasma half-lives, plasma metabolites and anticoagulant efficacies of the enantiomers of warfarin in man. J Pharm Pharmacol 25: 458–465
Jackson JE, Bentley JB, Glass S, Banner W, Plachetka JD (1983) The effect of H2-blockers on lignocaine disposition. Clin Pharmacol Ther 33: 255
Kirch W, Hoensch H, Janisch HD (1984) Interactions and non-interactions with ranitidine. Clin Pharmacokinet 9: 493–510
Lewis RJ, Trager WF, Chan KK, Breckenridge A, Orme M, Rowland M, Schary W (1974) Warfarin: Stereochemical aspects of its metabolism and the interaction with phenylbutazone. J Clin Invest 53: 1607–1617
Loeliger EA, Van Der Esch B, Mattern MJ, Den Brabander ASA (1963) Behaviour of Factors II, VII, IX and X during long-term treatment with coumarin. Thromb Diathes Haemorrh 9: 75–89
Nagashima R, Levy G (1979) Comparative pharmacokinetics of coumarin anticoagulants V: Kinetics of warfarin elimination in the rat, dog, rhesus monkey, compared to man. J Pharm Sci 58: 845–849
O'Reilly RA (1984) Comparative interaction of cimetidine and ranitidine with racemic warfarin in man. Arch Intern Med 144: 989–991
Powell JR, Donn KH (1984) Histamine H2-antagonist drug interactions in perspective: Mechanistic concepts and clinical implications. Am J Med 77: 57–84
Quick AJ (1966) Haemorrhagic diseases and thrombosis, 2nd edn. Lea and Febiger, Philadelphia, pp 391–395
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
Serlin MJ, Sibeon RG, Breckenridge AM (1981) Lack of effect of ranitidine on warfarin action. Br J Clin Pharmacol 12: 791–794
Serlin MJ (1982) Ranitidine and cimetidine: Interactions with other drugs. In: Wormsley MJJ (ed) The clinical use of ranitidine. The Medicine Publishing Foundation, pp 89–96
Silver BA, Bell WR (1979) Cimetidine potentiation of the hypoprothrombinemic effect of warfarin. Ann Intern Med 90: 348–349
Somogyi A, Bochner F (1984) Dose and concentration dependent effect of ranitidine on procainamide disposition and renal clearance in man. Br J Clin Pharmacol 18: 175–181
Toon S, Trager WF (1984) Pharmacokinetic implications of stereoselective changes in plasma-protein binding: Warfarin/sulfinipyrazone. J Pharm Sci 73: 1671–1673
Toon S, Low LK, Gibaldi M, Trager WF, O'Reilly RA, Motley CH, Goulart DA (1986) The warfarin/sulfinpyrazone interaction: Stereochemical considerations. Clin Pharmacol Ther 39: 15–24
Wilkinson CF, Hetnarski K, Hicks IJ (1974) Substituted imidazoles as inhibitors of microsomal oxidation and insecticide synergists. Pesticide Biochem Physiol 4: 299–312
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Toon, S., Hopkins, K.J., Garstang, F.M. et al. Comparative effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin in man. Eur J Clin Pharmacol 32, 165–172 (1987). https://doi.org/10.1007/BF00542190
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00542190