Toxicokinetic assessment of methylphenidate (Ritalin) enantiomers in pregnant rats and rabbits.
Ritalin or methylphenidate (MPH) is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. The present report describes the determination of plasma concentrations of D-threo- and L-threo-enantiomers of MPH in toxicokinetic (TK) studies in pregnant Wistar Hannover rats and New Zealand white rabbits following repeated daily oral dosing of D,L-MPH (racemate). A previously reported chiral liquid chromatography tandem mass spectrometric (LC-MS/MS) method with a lower limit of quantification (LLOQ) of 1.09 ng/mL was utilized. Oral (gavage) doses of 7, 25 and 75 mg/kg/day of racemic MPH were selected for the rat study. An over-proportional increase in exposure was observed with increasing doses of MPH racemate, the effect being more profound with the D- than the L-enantiomer. In contrast, Cmax values of both enantiomers were approximately proportional to the dose. Oral (gavage) doses of 20, 60 and 200 mg/kg were selected for the rabbit study. In general, for the D-isomer, an over-proportional increase in exposure was observed with increasing doses of MPH racemate. Conversely, for the L-isomer, a slight under-proportionality was detected in exposure with increasing doses of D,L-MPH. For mean Cmax, while L-isomer exhibited dose proportionality with increasing doses of MPH racemate, the D-isomer appeared to be over-proportional. Herein, the experimental design and observed TK parameters in each study are presented.
Bakhtiar
Ray
R
Novartis Institute for Biomedical Research, One Health Plaza, East Hanover, NJ 07936, USA. ray_bakhtiar@merck.com
Tse
Francis L S
FL
D000818:Animals; D000697:Central Nervous System Stimulants / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008774:Methylphenidate / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D013237:Stereoisomerism
D000697:Central Nervous System Stimulants; D008774:Methylphenidate