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