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Studies on Their Pharmacokinetics and Distribution in the Human Brain

Nora D. Volkow, MD; Yu-Shin Ding, PhD; Joanna S. Fowler, PhD; Gene-Jack Wang, MD; Jean Logan, PhD; John S. Gatley, PhD; Stephen Dewey, PhD; Charles Ashby, PhD; Jeffrey Liebermann, MD; Robert Hitzemann, PhD; Alfred P. Wolf, PhD

Arch Gen Psychiatry. 1995;52(6):456-463.

Abstract
Background
The purposes of this study were to investigate the pharmacokinetics of methylphenidate hydrochloride (Ritalin) in the human brain, to compare them with those of cocaine, and to evaluate whether cocaine and methylphenidate compete for the same binding sites.

Methods
We used positron emission tomography to measure the temporal and spatial distribution of carbon 11 (11C)-labeled methylphenidate. These results were compared with those obtained previously for [11C]cocaine. Eight healthy male subjects, 20 to 51 years of age, were scanned with [11C]methylphenidate. Three were tested twice to assess test-retest variability, four were tested at baseline and after administration of methylphenidate, and one was tested with [11C]methylphenidate and [11C]cocaine. Two baboons were scanned to evaluate whether there was competition between cocaine and methylphenidate for the same binding sites in the brain.

Results
The uptake of [¹¹C] methylphenidate in the brain was high (mean±SD, 7.5%±1.5%), and the maximal concentration occurred in striatum. Pretreatment with methylphenidate decreased binding only in striatum (40%). Although the regional distribution of [¹¹C]methylphenidate was identical to that of [¹¹C] cocaine and they competed with each other for the same binding sites, these two drugs differed markedly in their pharmacokinetics. Clearance of [¹¹C]methlphenidate from striatum (90 minutes) was significantly slower than that of [¹¹C]cocaine (20 minutes). For both drugs, their fast uptake in striatum paralleled the experience of the "high." For methylphenidate, the high decreased very rapidly despite significant binding of the drug in the brain. In contrast, for cocaine, the decline in the high paralleled its fast rate of clearance from the brain.

Conclusion
We speculate that because the experience of the high is associated with the fast uptake of cocaine and methylphenidate in the brain, the slow clearance of methylphenidate from the brain may serve as a limiting factor in promoting its frequent self-administration.

Author Affiliations
From the Medical Department (Drs Volkow, Wang, and Ashby), the Chemistry Department (Drs Ding, Fowler, Logan, Gatley, Dewey, and Wolf), Brookhaven National Laboratory, Upton, NY; the Department of Psychiatry, State University of New York—Stony Brook (Drs Volkow and Hitzemann); and Hillside Hospital, Glen Oaks, NY (Dr Liebermann).

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