title: Toxicokinetic assessment of methylphenidate (Ritalin) enantiomers in pregnant rats and rabbits.
abstract: 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.
authors.affiliation: Novartis Institute for Biomedical Research, One Health Plaza, East Hanover, NJ 07936, USA. ray_bakhtiar@merck.com
authors.forename: Ray
authors.initials: R
authors.lastname: Bakhtiar
authors.forename: Francis L S
authors.initials: FL
authors.lastname: Tse
mesh_terms: 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
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate