Niopas I, Toon S, Aarons L, Rowland M
Department of Pharmacy, Aristotle University of Thessaloniki, Greece.
Eur J Clin Pharmacol. 1999 Jul;55(5):399-404. doi: 10.1007/s002280050647.
The interaction of multiple oral doses of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin was investigated in six healthy male volunteers.
The subjects were given individually adjusted doses of warfarin to achieve therapeutic levels of prothrombin activity. The established daily maintenance oral dose of warfarin was kept stable throughout the trial and, on study days 8-14, each volunteer received a 800-mg daily dose of cimetidine. The degree of anticoagulant response produced by warfarin was quantified by the determination of both the prothrombin time and factor-VII clotting activity.
Cimetidine co-administration had no significant effect on the pharmacokinetics of the more potent S-warfarin but significantly increased by 28% (P < 0.05) mean R-warfarin trough plasma concentrations and decreased by 23% (P < 0.05) mean R-warfarin apparent clearance. Both prothrombin time and factor-VII clotting activity displayed considerable inter-subject variability and were not significantly affected by concurrent cimetidine treatment. The reduction of apparent clearance of R-warfarin by cimetidine was found to be the effect of inhibition of the formation of warfarin metabolites as determined by apparent formation clearance values (+/-SD) of R-6-hydroxywarfarin (31.1+/-7.4 ml/h baseline; 18.5+/-4.5 ml/h at end of cimetidine treatment; P < 0.01), and R-7-hydroxywarfarin (6.9+/-1.3 ml/h baseline; 4.3+/-1.1 ml/h at end of cimetidine treatment; P < 0.01).
Cimetidine stereoselectively affects the steady-state pharmacokinetics of warfarin by inhibiting the disposition of the less potent R-warfarin in humans. However, this interaction is likely to be of minimal clinical significance in most patients.
在6名健康男性志愿者中研究多次口服西咪替丁对华法林稳态药代动力学和药效学的相互作用。
给予受试者个体化调整剂量的华法林以达到凝血酶原活性的治疗水平。在整个试验过程中，既定的华法林每日维持口服剂量保持稳定，在研究的第8 - 14天，每位志愿者接受每日800 mg的西咪替丁剂量。通过测定凝血酶原时间和因子VII凝血活性来量化华法林产生的抗凝反应程度。
联合使用西咪替丁对活性更强的S - 华法林的药代动力学没有显著影响，但使R - 华法林的平均谷浓度显著升高28%（P < 0.05），并使R - 华法林的平均表观清除率降低23%（P < 0.05）。凝血酶原时间和因子VII凝血活性在受试者之间均表现出相当大的变异性，并且不受同时使用西咪替丁治疗的显著影响。西咪替丁导致R - 华法林表观清除率降低是由于抑制了华法林代谢产物的形成，这由R - 6 - 羟基华法林（基线时为31.1±7.4 ml/h；西咪替丁治疗结束时为18.5±4.5 ml/h；P < 0.01）和R - 7 - 羟基华法林（基线时为6.9±1.3 ml/h；西咪替丁治疗结束时为4.3±1.1 ml/h；P < 0.01）的表观形成清除率值（±标准差）确定。
西咪替丁通过抑制人体中活性较弱的R - 华法林的处置，立体选择性地影响华法林的稳态药代动力学。然而，这种相互作用在大多数患者中可能具有最小的临床意义。
