Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice.
Leflunomide is an immunosuppressive agent that inhibits de novo synthesis of pyrimidine nucleotides and the activity of protein tyrosine kinase. This study examined the teratogenicity of Leflunomide in mice. Pregnant mice were treated orally with Leflunomide at a dose of 10, 30 or 70 mg/kg/day from day 6 to 15 of pregnancy. At 70 mg/kg, all embryos were resorbed and no live fetuses were detected. At 30 mg/kg, Leflunomide reduced fetal viability, and increased the incidence of multiple external, skeletal and visceral malformations. Characteristic external malformations were neural tube defects, cleft palate and tail deformities. Limb malformations were observed in a small number of fetuses. Skeletal examinations revealed malformations of cervical to sacral vertebrae, ribs and sternebrae. In the viscerae, the main anomalies were membranous ventricular septum defect and persistent truncus arteriosus. The results of this study indicate that Leflunomide administered at 30 mg/kg on days 6 to 15 of pregnancy can induce craniofacial malformations and deformities of the axial skeleton, heart and great vessels in mice.
Fukushima
Ryou
R
Drug Safety Evaluation, Developmental Research Laboratories, Toyonaka, Osaka, Japan. ryou.fukushima@shionogi.co.jp
Kanamori
Susumu
S
Hirashiba
Masahiro
M
Hishikawa
Atsuko
A
Muranaka
Ri-Ich
RI
Kaneto
Masako
M
Nakamura
Kazuichi
K
Kato
Ikuo
I
D000014:Abnormalities, Drug-Induced; D000276:Adjuvants, Immunologic / Q000633:toxicity*; D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000002:abnormalities / Q000187:drug effects; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects; D019465:Craniofacial Abnormalities / Q000139:chemically induced / Q000196:embryology; D004305:Dose-Response Relationship, Drug; D020964:Embryo Loss; D005260:Female; D005327:Fetal Resorption; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000196:embryology; D007555:Isoxazoles / Q000633:toxicity*; D000077339:Leflunomide; D008297:Male; D051379:Mice; D011247:Pregnancy; D013723:Teratogens / Q000145:classification / Q000633:toxicity*
D000276:Adjuvants, Immunologic; D007555:Isoxazoles; D013723:Teratogens; D000077339:Leflunomide