Quantification of methylphenidate in rat, rabbit and dog plasma using a chiral liquid-chromatography/tandem mass spectrometry method - Application to toxicokinetic studies

Ritalin or methylphenidate (MPH) is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. The present report concerns the development and validation of an enantioselective reversed-phase liquid-chromatography/tandem mass spectrometry (LC/MS/MS) method, which was used in the determination of plasma concentrations of D- and L-antipodes of MPH in toxicokinetic (TK) studies in rats, rabbits, and dogs, following repeated daily oral dosing for up to 13 weeks. The sample processing involved the addition of sodium bicarbonate (1.0 M, pH 10) to plasma followed by liquid-liquid extraction using cyclohexane. Vancomycin, an amphoteric macrocyclic glycopeptide, produced by Streptomyces orientalis proved to be a rugged chiral selector for LC/MS/MS analysis of MPH. In all species, MPH appeared to be rapidly absorbed (T-max = 0.5-2h). Generally, the plasma exposure (area under the plasma concentration-time curve (AUC) and C-max)) of MPH was over-proportional to the dose. No differences in TK of MPH were observed between male and female dogs whereas in rats, females generally exhibited a slightly higher level of exposure than males. No unusual level of accumulation of MPH inconsistent with previously reported half-life (T-1/2 similar to 2.5h) of this compound was observed. (C) 2002 Elsevier Science B.V. All rights reserved.