title: Teratogenicity study of the dihydroorotate-dehydrogenase inhibitor and protein tyrosine kinase inhibitor Leflunomide in mice.
abstract: 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.
authors.affiliation: Drug Safety Evaluation, Developmental Research Laboratories, Toyonaka, Osaka, Japan. ryou.fukushima@shionogi.co.jp
authors.forename: Ryou
authors.initials: R
authors.lastname: Fukushima
authors.forename: Susumu
authors.initials: S
authors.lastname: Kanamori
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hirashiba
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hishikawa
authors.forename: Ri-Ich
authors.initials: RI
authors.lastname: Muranaka
authors.forename: Masako
authors.initials: M
authors.lastname: Kaneto
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Nakamura
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kato
mesh_terms: 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*
chemical_list: D000276:Adjuvants, Immunologic; D007555:Isoxazoles; D013723:Teratogens; D000077339:Leflunomide