Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity

Williard, Robin L.^b; Middaugh, Lawrence D.^{b c}; Zhu, Hao-Jie B.^a; Patrick, Kennerly S.^a

Departments of^aPharmaceutical Sciences

^bNeurosciences

^cPsychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina, USA

Correspondence to Professor Emeritus Lawrence D. Middaugh, PhD, Psychiatry and Behavioral Science, Center for Drug and Alcohol Programs, Medical University of South Carolina, 67 President Street, Charleston, SC 29482, USA.

E-mail:[email protected]

Received 16 June 2006 Accepted as revised 23 October 2006

Behavioural Pharmacology18(1):p 39-51, February 2007. |DOI:10.1097/FBP.0b013e3280143226

Abstract

Ethylphenidate is formed by metabolic transesterification of methylphenidate and ethanol. Study objectives were to (a) establish that ethylphenidate is formed in C57BL/6 (B6) mice; (b) compare the stimulatory effects of ethylphenidate and methylphenidate enantiomers; (c) determine methylphenidate and ethylphenidate plasma and brain distribution and (d) establish in-vitro effects of methylphenidate and ethylphenidate on monoamine transporter systems. Experimental results were that: (a) coadministration of ethanol with the separate methylphenidate isomers enantioselectively produced l-ethylphenidate; (b) d and dl-forms of methylphenidate and ethylphenidate produced dose–responsive increases in motor activity with stimulation being less for ethylphenidate; (c) plasma and whole-brain concentrations were greater for ethylphenidate than methylphenidate and (d) d and DL-methylphenidate and ethylphenidate exhibited comparably potent low inhibition of the dopamine transporter, whereas ethylphenidate was a less potent norepinephrine transporter inhibitor. These experiments establish the feasibility of the B6 mouse model for examining the interactive effects of ethanol and methylphenidate. As reported for humans, concurrent exposure of B6 mice to methylphenidate and ethanol more readily formed l-ethylphenidate than d-ethylphenidate, and the l-isomers of both methylphenidate and ethylphenidate were biologically inactive. The observed reduced stimulatory effect of d-ethylphenidate relative to d-methylphenidate appears not to be the result of brain dispositional factors, but rather may be related to its reduced inhibition of the norepinephrine transporter, perhaps altering the interaction of dopaminergic and noradrenergic neural systems.