Inhibiting the teratogenicity of the immunosuppressant leflunomide in mice by supplementation of exogenous uridine.
Leflunomide is an immunosuppressant drug displaying teratogenicity in mice, rats, and rabbits. Its immunosuppressive effect occurs via inhibition of dihydroorotate dehydrogenase (DHODH) and tyrosine kinases. In this study, we coadministered Leflunomide and uridine, a precursor substance of pyrimidine nucleotides, to pregnant CD-1 mice, and examined whether or not a decreased level of intracellular pyrimidine nucleotides with inhibition of DHODH is related to the teratogenicity of Leflunomide. Then we examined the alteration of the nucleotide level in fetal tissue by Leflunomide and the effect of coadministered uridine. We administered Leflunomide with or without uridine to pregnant mice on gestation day 10, and used the vehicle of Leflunomide as a control. Leflunomide caused multiple malformations in all fetuses, but coadministration with uridine inhibited most of its teratogenicity. Leflunomide decreased the concentration of pyrimidine nucleotides, not purine nucleotides, whereas uridine coadministered with Leflunomide partially restored the level of pyrimidine nucleotides. These results indicate that the inhibitory effect of DHODH activity is related to the teratogenicity of Leflunomide.
Fukushima
Ryou
R
Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co, Ltd, Toyonaka, Osaka, Japan. ryou.fukushima@shionogi.co.jp
Kanamori
Susumu
S
Hirashiba
Masahiro
M
Hishikawa
Atsuko
A
Muranaka
Ri-ichi
R
Kaneto
Masako
M
Kitagawa
Hiroshi
H
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000818:Animals; D000090722:Dihydroorotate Dehydrogenase; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D005328:Fetal Viability / Q000187:drug effects; D005333:Fetus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D007555:Isoxazoles / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000077339:Leflunomide; D051379:Mice; D008813:Mice, Inbred ICR; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000378:metabolism; D011247:Pregnancy; D011742:Pyrimidine Nucleotides / Q000378:metabolism; D013723:Teratogens; D014529:Uridine / Q000494:pharmacology*
D000090722:Dihydroorotate Dehydrogenase; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D011742:Pyrimidine Nucleotides; D013723:Teratogens; D044925:Oxidoreductases Acting on CH-CH Group Donors; D000077339:Leflunomide; D014529:Uridine