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 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.
Footnotes
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This work was supported by National Institute of Child Health and Human Development Grant R21HD047810-01 and by National Institutes of Health Grant C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.009605.
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ABBREVIATIONS: ADHD, attention-deficit/hyperactive disorder; MPH, methylphenidate; AMP, amphetamine; ABC, ATP-binding cassette; P-gp, p-glycoprotein; MDR/mdr, multidrug resistance; BBB, blood-brain barrier; CNS, central nervous system; KO, knockout; WT, wild type; ANOVA, analysis of variance; GC-MS, gas chromatography-mass spectrometry; HPLC, high-performance liquid chromatography; WTV, wild type injected with vehicle; WTD, wild type injected with drug; P-gp KOV, P-gp KO mice injected with vehicle; P-gp KOD, P-gp KO mice injected with drug.
- Received February 2, 2006.
- Accepted April 13, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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