(R)-(+)-Warfarin

(R)-(+)-Warfarin is an orally active chiral 4-hydroxycoumarin compound with vitamin K epoxide reductase (VKOR) inhibitory activity and cytochrome P450 substrate activity. (R)-(+)-Warfarin undergoes stereoselective metabolism via CYP1A2 to form 6-Hydroxywarfarin and 8-Hydroxywarfarin, and is metabolized via CYP3A4 to produce 10-Hydroxywarfarin (HY-134999). (R)-(+)-Warfarin can be used for the research of thromboembolic diseases^[1][2]. In Vitro:(R)-(+)-Warfarin acts as a stereoselective substrate for polymorphic recombinant human CYP450 enzymes. Wild-type CYP1A1 and its Ile462 and Val462 mutants, as well as CYP1A2, respectively catalyze the 6/8-hydroxylation of (R)-(+)-Warfarin, exhibiting differential regioselectivity and K_m values. CYP2C19 mediates 8-hydroxylation but shows low expression in the liver, while CYP3A4, which has high hepatic abundance, catalyzes 10-hydroxylation and serves as the major metabolic enzyme in vivo^[1].
(R)-(+)-Warfarin competitively inhibits CYP2C9-mediated metabolism of S-Warfarin in human liver microsomes, with a K_i value of 6-6.9 μM; additionally, it is stereoselectively reduced by NADPH-dependent carbonyl reductases in human liver and kidney to form R,S-warfarin alcohol, and the cytosolic enzyme fraction accounts for the majority of the reductive activity^[1].
(R)-(+)-Warfarin inhibits vitamin K reductase and vitamin K₁ epoxide reductase in Wistar rat liver microsomes; it is metabolized by cytochrome P-450 enzymes into multiple oxidative metabolites in human liver microsomes^[2].
(R)-(+)-Warfarin binds extensively to human serum albumin, and its binding affinity is lower than that of (S)-warfarin^[2]. In Vivo:(R)-(+)-Warfarin exhibits lower anticoagulant potency and acute toxicity in rats than (S)-warfariny^[2].
(R)-(+)-Warfarin (daily; from 2 days pre-implant until study end) does not inhibit primary tumour growth or lung metastasis in mice bearing Lewis lung carcinoma, and does not produce measurable anticoagulant effects in this model^[2].
(R)-(+)-Warfarin produces a longer-lasting anticoagulant response in rabbits than (S)-warfarin, even though it is less potent on a plasma concentration basis^[2].