Abstract
The baboon is potentially an attractive animal for modeling 3,4-methylenedioxymethamphetamine (MDMA) effects in humans. Baboons self-administer MDMA, are susceptible to MDMA neurotoxicity, and are suitable for positron emission tomography, the method most often used to probe for MDMA neurotoxicity in humans. Because pharmacokinetic equivalence is a key feature of a good predictive animal model, we compared the pharmacokinetics of MDMA in baboons and humans. Baboons were trained to orally consume MDMA. Then, pharmacokinetic profiles of MDMA and its major metabolites were determined after various oral MDMA doses using the same analytical method recently used to perform similar studies in humans. Results indicate that MDMA pharmacokinetics after oral ingestion differ markedly between baboons and humans. Baboons had little or no MDMA in their plasma but had high plasma concentrations of 3,4-dihydroxymethamphetamine (HHMA), pointing to much more extensive first-pass metabolism of MDMA in baboons than in humans. Other less prominent differences included less O-methylation of HHMA to 4-hydroxy-3-methoxymethamphetamine, greater N-demethylation of MDMA to 3,4-methylenedioxyamphetamine, and a shorter half-life of HHMA in the baboon. To our knowledge, this is the first study to characterize MDMA metabolism and disposition in the baboon. Differences in MDMA pharmacokinetics between baboons and humans suggest that the baboon may not be ideal for modeling human MDMA exposure. However, the unusually rapid conversion of MDMA to HHMA in the baboon may render this animal uniquely useful for clarifying the relative role of the parent compound (MDMA) versus metabolites (particularly HHMA) in the biological actions of MDMA.
Footnotes
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants DA05707, DA01796401, DA021616 and Contract N01-DA87071] (to G.R. and N.A., respectively).
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.180612.
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ABBREVIATIONS:
- MDMA
- 3,4-methylenedioxymethamphetamine
- HHMA
- 3,4-dihydroxymethamphetamine
- HMMA
- 4-hydroxy-3-methoxymethamphetamine
- MDA
- 3,4-methylenedioxyamphetamine
- Cmax
- peak plasma concentration
- Tmax
- time of peak plasma concentration
- AUC
- area under the concentration-time curve
- COMT
- catechol O-methyltransferase.
- Received February 14, 2011.
- Accepted April 4, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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