Beckman David A, Schneider Marilynn, Youreneff Maureen, Tse Francis L S
Preclinical Safety, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA.
Birth Defects Res B Dev Reprod Toxicol. 2008 Oct;83(5):489-501. doi: 10.1002/bdrb.20168.
Previous investigations reported no teratogenicity for methylphenidate (MPH). These studies investigated potential teratogenicity of d-MPH and d,l-MPH as commitments to the FDA.
Rabbits received 15, 50, 150 mg/kg/day (mkd) d-MPH or 20, 60, 200, 300 mkd d,l-MPH on gestation days 7-20. Rats received 2.5, 10, 40 mkd d-MPH, or 7, 25, 75, 80 mkd d,l-MPH on gestation days 6-17.
d-MPH-In rabbits, mortality occurred at 150 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at >or=15 mkd in rabbits and >or=10 mkd in rats. Decreased food consumption occurred at 40 mkd in rats. Decreased body weight parameters occurred at 150 mkd in rabbits and >or=10 mkd in rats. There were no fetal findings in rabbits. In rats, skeletal variations occurred at 40 mkd. d,l-MPH-In rabbits, mortality occurred at >or=200 mkd. Dilated pupils, increased activity, biting/chewing, respiration, and salivation occurred at >or=20 mkd in rabbits and >or=25 mkd in rats. Decreased food consumption occurred at >or=200 mkd in rabbits and >or=25 mkd in rats. Decreased body weight parameters occurred at >or=200 mkd in rabbits and >or=25 mkd in rats. In rabbits, two fetuses (separate litters) had spina bifida and malrotated hindlimbs at 200 mkd. In rats, skeletal variations occurred at >or=75 mkd.
There was no teratogenicity with d-MPH. There was a low teratogenic risk with d,l-MPH in only the rabbit. Higher C(max) may explain differences in results from previous studies.
先前的研究报告称哌甲酯（MPH）无致畸性。这些研究作为对美国食品药品监督管理局（FDA）的承诺，调查了右旋哌甲酯（d-MPH）和消旋哌甲酯（d,l-MPH）的潜在致畸性。
在妊娠第7至20天，给兔子分别给予15、50、150毫克/千克/天（mkd）的d-MPH或20、60、200、300 mkd的d,l-MPH。在妊娠第6至17天，给大鼠分别给予2.5、10、40 mkd的d-MPH，或7、25、75、80 mkd的d,l-MPH。
d-MPH——在兔子中，150 mkd时出现死亡。在兔子中，≥15 mkd时出现瞳孔散大、活动增加、咬/嚼、呼吸和流涎，在大鼠中≥10 mkd时出现这些情况。在大鼠中，40 mkd时出现食物消耗减少。在兔子中，150 mkd时出现体重参数下降，在大鼠中≥10 mkd时出现体重参数下降。兔子中未发现胎儿异常。在大鼠中，40 mkd时出现骨骼变异。d,l-MPH——在兔子中，≥200 mkd时出现死亡。在兔子中，≥20 mkd时出现瞳孔散大、活动增加、咬/嚼、呼吸和流涎，在大鼠中≥25 mkd时出现这些情况。在兔子中，≥200 mkd时出现食物消耗减少，在大鼠中≥25 mkd时出现食物消耗减少。在兔子中，≥200 mkd时出现体重参数下降，在大鼠中≥25 mkd时出现体重参数下降。在兔子中，200 mkd时，有两只胎儿（来自不同窝）出现脊柱裂和后肢旋转不良。在大鼠中，≥75 mkd时出现骨骼变异。
d-MPH无致畸性。仅在兔子中，d,l-MPH有致畸风险较低。较高的血药浓度峰值（C(max)）可能解释了与先前研究结果的差异。
