Summary
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 × 10−4 × Hr−1 mean ± SEM; on halofenate = 268 ± 39 × 10−4 × Hr−1 mean ± SEM; P < 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 < 0.001). Cessation of halofenate
from combined therapy results 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.
