Alterations in the effects of warfarin in dogs by halofenate: an influence upon the kinetics of prothrombin.

M Weintraub, P F Griner
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Abstract

The interaction between warfarin and the new lipid lowering agent halofenate (MK 185) [2- acetamidoethyl (p-chlorophenyl) (m-trifluoromethylphenoxy) acetate] was studied in dogs in both short- and long-term experiments. Our data suggest that halofenate potentiates the anticoagulant effect of warfarin by increasing the degradation of prothrombin (factor II) (Kdeg on placebo = 211 +/- 32 X 10(-4) X Hr-1 mean +/- SEM; on halofenate = 268 +/- 39 X 10(-4) X Hr-1 mean +/- SEM; P less than 0.01). However, a concomitant increase in factor II synthesis of 34% results in resistance to warfarin's effect if halofenate is administered prior to warfarin. The mean prothrombin time of 4 dogs on 2 mg of warfarin following halofenate pretreatment for 8 weeks was 74.8% +/- 17.3 (SE) of the anticoagulated control dog. On 2 mg of warfarin alone, it was 133.7% +/- 42.0 (P less than 0.001). Cessation of halofenate from combined therapy resulted in a delayed augmentation of warfarin effect. These data suggest that the nature of the interaction between warfarin and drugs such as halofenate which alter the kinetics of prothrombin may depend on the sequence of administration.

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盐芬酸盐对华法林在狗体内作用的改变:对凝血酶原动力学的影响。
研究了华法林与新型降脂剂卤芬酸盐(MK 185)[2-乙酰氨基乙基(对氯苯基)(间三氟甲基苯氧基)醋酸酯]在狗体内的短期和长期相互作用。我们的数据表明,氟化萘酸通过增加凝血酶原(因子II)的降解来增强华法林的抗凝作用(Kdeg在安慰剂上= 211 +/- 32 X 10(-4) X Hr-1平均+/- SEM;对卤代盐= 268 +/- 39 X 10(-4) X Hr-1平均+/- SEM;P < 0.01)。然而,如果在华法林之前使用氟化萘酸盐,则伴随因子II合成增加34%,导致对华法林作用的耐药性。氟化萘酸盐预处理8周后,4只使用华法林2 mg的狗平均凝血酶原时间为抗凝对照组的74.8% +/- 17.3 (SE)。单独使用华法林2 mg时,阳性/阴性为133.7% (P < 0.001)。停止氟化萘酸联合治疗导致华法林效应的延迟增强。这些数据表明华法林与改变凝血酶原动力学的药物(如氟化萘酸盐)之间相互作用的性质可能取决于给药顺序。
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Fibrinogen and fibrin degradation products: their differentiation. Urinary fibrin/fibrinogen derivatives. On the structure of fibrinogen related to its plasmic degradation products D and E. The position of long-term stimulation of the endogenous fibrinolytic system: present achievements and clinical perspectives. Culture of arterial endothelial cells: characterization and growth of bovine aortic cells.
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