Sex differences in the kinetic profiles of d- and l- methylphenidate in the brains of adult rats

Abstract

Objective: Methylphenidate is commonly used in the treatment of Attention Deficit Hyperactivity Disorder and narcolepsy. Methylphenidate is administered as a racemic mixture of the d- and l- threo enantiomers; however, the d-enantiomer is primarily responsible for the pharmacologic activity. Previous studies of the behavioral effects of methylphenidate have highlighted sex differences in the responsiveness to the drug, namely an increased sensitivity of females to its stimulatory effects. These differences may be due to differences in the uptake, distribution, and elimination of methylphenidate from male and female brains. Therefore, we compared the pharmacokinetics of d- and l- threo methylphenidate in the brains of male and female rats.

Materials and methods: Adult male and female Sprague-Dawley rats were injected with 5 mg/kg d, l- threo methylphenidate, and whole brains were collected at various time points following injection. We measured methylphenidate concentrations utilizing chiral high pressure liquid chromatography followed by mass spectrometry.

Results: Females exhibited consistently higher brain concentrations of both d- and l- methylphenidate and a slower clearance of methylphenidate from brain as compared to males, particularly with the active d-enantiomer.

Conclusions: The increased sensitivity of females to methylphenidate may be partially explained by an increase in total brain exposure to the drug.