PET studies of d-methamphetamine pharmacokinetics in primates: Comparison with l-methamphetamine and (-)-cocaine

Joanna S. Fowler, Carsten Kroll, Richard Ferrieri, David Alexoff, Jean Logan, Stephen L. Dewey, Wynne Schiffer, David Schlyer, Pauline Carter, Payton King, Colleen Shea, Youwen Xu, Lisa Muench, Helene Benveniste, Paul Vaska, Nora D. Volkow

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

The methamphetamine molecule has a chiral center and exists as 2 enantiomers, d-methamphetamine (the more active enantiomer) and l-methamphetamine (the less active enantiomer). d-Methamphetamine is associated with more intense stimulant effects and higher abuse liability. The objective of this study was to measure the pharmacokinetics of d-methamphetamine for comparison with both l-methamphetamine and (-)-cocaine in the baboon brain and peripheral organs and to assess the saturability and pharmacologic specificity of binding. Methods: d- and l-methamphetamine and (-)-cocaine were labeled with 11C via alkylation of the norprecursors with 11C-methyl iodide using literature methods. Six different baboons were studied in 11 PET sessions at which 2 radiotracer injections were administered 2-3 h apart to determine the distribution and kinetics of 11C-d-methamphetamine in brain and peripheral organs. Saturability and pharmacologic specificity were assessed using pretreatment with d-methamphetamine, methylphenidate, and tetrabenazine. 11C-d-Methamphetamine pharmacokinetics were compared with 11C-l-methamphetamine and 11C-(-)-cocaine in both brain and peripheral organs in the same animal. Results: 11C-d- and l-methamphetamine both showed high uptake and widespread distribution in the brain. Pharmacokinetics did not differ between enantiomers, and the cerebellum peaked earlier and cleared more quickly than the striatum for both. 11C-d-Methamphetamine distribution volume ratio was not substantially affected by pretreatment with methamphetamine, methylphenidate, or tetrabenazine. Both enantiomers showed rapid, high uptake and clearance in the heart and lungs and slower uptake and clearance in the liver and kidneys. A comparison of 11C-d-methamphetamine and 11C-(-)-cocaine showed that 11C-d-methamphetamine peaked later in the brain than did 11C-(-)-cocaine and cleared more slowly. The 2 drugs showed similar behavior in all peripheral organs examined except the kidneys and pancreas, which showed higher uptake for 11C-d-methamphetamine. Conclusion: Brain pharmacokinetics did not differ between d-and l-methamphetamine and thus cannot account for themore intense stimulant effects of d-methamphetamine. Lack of pharmacologic blockade by methamphetamine indicates that the PET image represents nonspecific binding, though the fact that methamphetamine is both a transporter substrate and an inhibitor may also play a role. A comparison of 11C-d-methamphetamine and 11C-(-)-cocaine in the same animal showed that the slower clearance of methamphetamine is likely to contribute to its previously reported longer-lasting stimulant effects relative to those of (-)-cocaine. High kidney uptake of d-methamphetamine or its labeled metabolitesmay account for the reported renal toxicity of d-methamphetamine in humans.

Original languageEnglish (US)
Pages (from-to)1724-1732
Number of pages9
JournalJournal of Nuclear Medicine
Volume48
Issue number10
DOIs
StatePublished - Oct 1 2007

Keywords

  • Brain
  • C
  • Methamphetamine
  • PET
  • Peripheral organs

Fingerprint Dive into the research topics of 'PET studies of d-methamphetamine pharmacokinetics in primates: Comparison with l-methamphetamine and (-)-cocaine'. Together they form a unique fingerprint.

Cite this