Leflunomide

Biological Activity

Leflunomide is an inhibitor of dihydroorotate dehydrogenase with IC50 of 2.5 μM. Leflunomide inhibits de novo pyrimidine synthesis in human T-cells in vitro. Leflunomide also inhibits lymphocyte proliferation. The inhibition of human DHODH by A77 1726, the active metabolite of leflunomide, occurs at levels (approximately 600 nM) that are achieved during treatment of rheumatoid arthritis (RA).

Chemical Information

Molecular Weight	270.21
Formula	C12H9F3N2O2
CAS Number	75706-12-6
Solubility (25°C)	DMSO 40 mg/mL Ethanol 10 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Davis JP, et al. Biochemistry. The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase.

[2] Xu X, et al. J Biol Chem. Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide.