In vitro assessment of teratogenic potential of cis-1-[4-(p-menthane-8-yloxy) phenyl]piperidine [corrected].
Teratogenic potential of cis-1-[4-(p-menthane-8-yloxy) phenyl] piperidine [corrected] (YM9429) was assessed by in vitro culture method using fetal palatal tissues of CD rats. YM9429 induced fetal cleft palate in vivo in CD rats when dams were orally treated during days 11-14 of pregnancy at dose of 500 mg/kg/day, but no abnormalities were detected when treated on days 15-16 (Shibata, 1993). After 4 successive days oral treatment during days 11-14 of pregnancy, the maternal plasma levels of the drug were less than 5 micrograms/ml on day 15 and less than 1 microgram/ml on day 16. After a single oral dosing on day 14, the fetal levels were approximately 0.3 microgram/g-fetus at 2 hours post dosing. When the fetal maxillary regions removed from the normal fetuses on day 15 of pregnancy were cultured with YM9429 at the concentrations of 5 and 1 micrograms/ml-medium for 48 or 72 hours, normal and full contact of the palatal shelves was observed. These results supported the previous findings that YM9429 demonstrated no teratogenic effects in vivo by maternal treatment on days 15-16 of pregnancy, and suggested other mechanisms than the direct influences on the fetal palatal shelves in the latter phases of morphogenesis including reorientation, horizontal extension and adhesion.
Shibata
M
M
Safety Research Laboratories, Yamanouchi Pharmaceutical Co. Ltd., Tokyo, Japan.
Watanabe
T
T
D000818:Animals; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D005333:Fetus / Q000737:chemistry / Q000187:drug effects*; D010159:Palate / Q000187:drug effects / Q000196:embryology*; D010880:Piperidines / Q000032:analysis / Q000097:blood / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*
D010880:Piperidines; D013723:Teratogens; C084611:YM 9429