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Drug Metabolism and Disposition Fast Forward
First published on April 18, 2006; DOI: 10.1124/dmd.106.009605

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Received for publication February 3, 2006.
Revised April 12, 2006.
Accepted for publication April 13, 2006.

The Role of the Polymorphic Efflux Transporter P-glycoprotein on the Brain Accumulation of d-Methylphenidate and d-Amphetamine

HAO-JIE ZHU 1, Jun-Sheng Wang 2, C. Lindsay Devane 1, Robin L Williard 1, Jennifer L Donovan 1, Lawrence D Middaugh 1, Bryan B Gibson 1, Kennerly S Patrick 1, John S. Markowitz 3*

1 Medical University of South Carolina 2 Medical University of SouthCarolina 3 Medical University of South carolina

* Address correspondence to: E-mail: markowij{at}musc.edu

Abstract

The psychostimulant medications methylphenidate (MPH) and amphetamine (AMP), available in various ratios or enantiopure formulations of their respective active dextrorotary isomers, constitute the majority of agents employed in the treatment of attention-deficit/hyperactivity disorder (ADHD). Substantial inter-individual variability occurs in their pharmacokinetics and tolerabilty. Little is known regarding the potential role of drug transporters such as P-glycoprotein (P-gp) in psychostimulant PK and response. Accordingly, experiments were carried out in P-gp knockout (KO) mice versus wild-type (WT) mice following intraperitoneal dosing (2.5 mg/kg) of d-MPH or (3.0 mg/kg) of d-AMP. Following the administration of each psychostimulant, locomotor activity was assessed at 30-min intervals for two hours. Total brain-to-plasma drug concentration ratios were determined at 10, 30, 80 min post-dosing time points. The results showed no statistically supported genotypic difference in d-AMP-induced locomotor activity stimulation or in brain-to-plasma ratio of d-AMP. As for d-MPH, the P-gp KO mice had 33% higher brain concentrations (p<0.05) and 67.5% higher brain-to-plasma ratios (p<0.01) than WT controls at the 10 min post-dosing time point. However, in spite of elevated brain concentrations, d-MPH-induced locomotor activity increase was attenuated for P-gp compared to that for WT mice. These data indicate that P-gp has no apparent effect on the pharmacokinetics and pharmacodynamics of d-AMP. Additionally, d-MPH is a relatively weak P-gp substrate, and its entry into the brain may be limited by P-gp. Furthermore, the mechanism by which d-MPH-induced locomotor activity was attenuated in P-gp KO mice remains to be elucidated.


Key words: blood-brain barrier, drug transport, p-glycoprotein, pharmacokinetics, transgenic models




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