RT Journal Article SR Electronic T1 THE ROLE OF THE POLYMORPHIC EFFLUX TRANSPORTER P-GLYCOPROTEIN ON THE BRAIN ACCUMULATION OF d-METHYLPHENIDATE AND d-AMPHETAMINE JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1116 OP 1121 DO 10.1124/dmd.106.009605 VO 34 IS 7 A1 Hao-Jie Zhu A1 Jun-Sheng Wang A1 C. Lindsay DeVane A1 Robin L. Williard A1 Jennifer L. Donovan A1 Lawrence D. Middaugh A1 Brian B. Gibson A1 Kennerly S. Patrick A1 John S. Markowitz YR 2006 UL http://dmd.aspetjournals.org/content/34/7/1116.abstract AB 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 used in the treatment of attention-deficit/hyperactivity disorder (ADHD). Substantial interindividual variability occurs in their pharmacokinetics and tolerability. Little is known regarding the potential role of drug transporters such as P-glycoprotein (P-gp) in psychostimulant pharmacokinetics and response. Therefore, experiments were carried out in P-gp knockout (KO) mice versus wild-type (WT) mice after intraperitoneal dosing (2.5 mg/kg) of d-MPH or (3.0 mg/kg) of d-AMP. After the administration of each psychostimulant, locomotor activity was assessed at 30-min intervals for 2 h. Total brain-to-plasma drug concentration ratios were determined at 10-, 30-, and 80-min postdosing 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 postdosing timepoint. However, in spite of elevated brain concentrations, d-MPH-induced locomotor activity increase was attenuated for P-gp compared with that for WT mice. These data indicate that P-gp has no apparent effect on the pharmacokinetics and pharmacodynamics of d-AMP. In addition, 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. The American Society for Pharmacology and Experimental Therapeutics