Developmental toxicity assessment of d,l-methylphenidate and d-methylphenidate in rats and rabbits.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.