The role of the polymorphic efflux transporter P-glycoprotein on the brain accumulation of d-methylphenidate and d-amphetamine.
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.
Zhu
Hao-Jie
HJ
Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Wang
Jun-Sheng
JS
DeVane
C Lindsay
CL
Williard
Robin L
RL
Donovan
Jennifer L
JL
Middaugh
Lawrence D
LD
Gibson
Brian B
BB
Patrick
Kennerly S
KS
Markowitz
John S
JS
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003913:Dextroamphetamine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007274:Injections, Intraperitoneal; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000697:Central Nervous System Stimulants; D003913:Dextroamphetamine; D008774:Methylphenidate; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3; C507084:Abcb1b protein, mouse