Critical periods for the teratogenicity of immune-suppressant Leflunomide in mice.
Leflunomide has inhibitory effects on dihydroorotate-dehydrogenase activity and protein tyrosine kinase activity. In the present study, a single dose of 50 mg/kg Leflunomide was administered to pregnant mice on one of gestation days (GD)6-11. Characteristic external malformations were craniofacial defects following dosing on GD7, cleft palate on GD9, cleft palate and limb and tail deformities on GD10, and limb deformities on GD11. Skeletal examination revealed cervical to caudal vertebral malformations after treatment on GD7, GD8, GD9 or GD10. In the viscera, cardiovascular deformities were observed in the GD7 and GD9 Leflunomide-treated groups. These results demonstrate that multiple malformations were seen in various organs and most of the malformations observed appeared to be developmental stage-specific responses to Leflunomide treatment.
Fukushima
Ryou
R
Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co. Ltd., 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; D000015:Abnormalities, Multiple / Q000473:pathology*; D000276:Adjuvants, Immunologic / Q000633:toxicity; D000818:Animals; D003423:Critical Period, Psychological; D020964:Embryo Loss; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects*; D005260:Female; D005328:Fetal Viability / Q000187:drug effects*; D005865:Gestational Age; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007555:Isoxazoles / Q000633:toxicity*; D000077339:Leflunomide; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy
D000276:Adjuvants, Immunologic; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D000077339:Leflunomide