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Toxicokinetic assessment of methylphenidate (Ritalin ® ) in a 13‐week oral toxicity study in dogs
Author(s) -
Bakhtiar Ray,
Ramos Luis,
Tse Francis L. S.
Publication year - 2004
Publication title -
biomedical chromatography
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.4
H-Index - 65
eISSN - 1099-0801
pISSN - 0269-3879
DOI - 10.1002/bmc.290
Subject(s) - methylphenidate , chemistry , beagle , narcolepsy , oral administration , toxicity , toxicokinetics , pharmacology , chromatography , modafinil , attention deficit hyperactivity disorder , medicine , psychiatry , organic chemistry
Ritalin ® or methylphenidate (MPH) is often prescribed for the treatment of attention decit hyperactivity disorder (ADHD) and narcolepsy. The therapeutic activity of MPH is principally due to d ‐ threo ‐[2 R ,2′ R ]‐MPH. Hence, in order to establish a kinetic relationship between doses and exposure levels in a non‐rodent species, a 13‐week oral (capsule) toxicity study of d ‐ threo ‐[2 R ,2′ R ]‐MPH was performed in beagle dogs. A previously reported chiral liquid chromatography tandem mass spectrometry (LC‐MS/MS) with a limit of quantication (LLOQ) of 1.09 ng/ml was utilized. The results of this study indicated that MPH appeared to be rapidly absorbed in dogs following oral administration. The peak concentration was reached within 1–2 h. Based on the area under the curve (AUC) values, the plasma exposure of d ‐MPH was over‐proportional to the dose. With the exception of two groups of animals (male/female, 7.5 mg/kg/day on day 1 and male/female, 3.0 mg/kg/day on week 7), the data showed no difference in MPH concentrations between the male and female dogs. Taking the statistical variations into account, concentrations of d ‐MPH that were observed after 7.5 mg/kg/day doses of d ‐MPH and 15 mg/kg/day doses of the racemate were similar. Following the racemate doses, the concentrations of l ‐MPH were consistently higher than those of the d ‐isomer. No accumulation of MPH was observed after 13 weeks of repeated daily administration. Copyright © 2003 John Wiley & Sons, Ltd.