Juvenile toxicity assessment of d,l-methylphenidate in rats.
BACKGROUND
The oral administration of d,l-methylphenidate (MPH) was designed to encompass the major part of postnatal development in the rat and to evaluate potential chronic effects.


METHODS
Wistar Hannover rats were cross-fostered on postpartum day 0 (day of birth) and were administered MPH at doses of 5, 50, and 100 mg/kg/day (mpkd) on postpartum days 7 to 70. Clinical signs, body weight, food consumption, developmental, behavioral, clinical/anatomic pathology, toxicokinetic, and fertility evaluations were conducted.


RESULTS
MPH-related effects on clinical signs, body weight, and behavior tests were noted. Increased locomotor activity and cage biting/chewing occurred at > or =5 mpkd (females) and > or =50 mpkd (males) and were absent after dosing ceased. Body weight parameters were decreased at > or =50 mpkd and were comparable to controls at 5 weeks' recovery. Open field motor activity tests conducted 2 weeks after dosing ceased revealed decreased peripheral beam breaks at > or =50 mpkd. Passive avoidance tests conducted 3 weeks after dosing ceased indicated decreased females reaching learning criterion at 100 mpkd. This is considered of nominal significance as there were no effects in the water maze test or retention in passive avoidance test. After multiple doses, females exhibited higher exposures than males and exposures were reduced in all groups in comparison to those after a single dose.


CONCLUSIONS
These results suggest that MPH can produce enduring behavioral effects in rats. The no-toxicologic-effect-level was 5 mpkd, associated with AUC((0-24 h)) racemate values in males and females, respectively, of 101 and 153 ng.h/mL after chronic dosing.
Beckman
David A
DA
Safety Profiling & Assessment, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA. david.beckman@novartis.com
Schneider
Marilynn
M
Youreneff
Maureen
M
Tse
Francis L S
FL
D000818:Animals; D000831:Animals, Newborn; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005298:Fertility / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008774:Methylphenidate / Q000633:toxicity*; D009043:Motor Activity / Q000187:drug effects; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D000697:Central Nervous System Stimulants; D008774:Methylphenidate