Population pharmacokinetics of 3,4-methylenedioxymethamphetamine and main metabolites in rats.
Déborah Hirt, Julien Fonsart, Marie-Claude Menet, Marcel Debray, Florence Noble, Xavier Declèves, Jean-Michel Scherrmann
Toxicological sciences : an official journal of the Society of Toxicology March 2010 DOI: 10.1093/toxsci/kfp300 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical pharmacokinetic study in rats Peer reviewed |
|---|---|
| Sample size | 66 |
| Population | Rats (33 males and 33 females) |
| Interventions | MDMA MDA |
| Dose | 1 mg/kg MDMA iv; 1 mg/kg MDA |
| Measures | high-performance liquid chromatography-mass spectrometry |
| Topics | MDMA |
| Key points | An integrated six-compartment pharmacokinetic model adequately described MDMA, MDA, HMMA, and HMA concentrations over time in rats. Females had smaller MDMA distribution volumes and converted less MDMA to MDA than males, and male rats were exposed to significantly more MDA and HMA, which the authors propose may explain greater male sensitivity to MDMA toxicity. |
Abstract
The pharmacokinetics of the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) and its mains metabolites have never been modeled together. We therefore designed a model with which to analyze the pharmacokinetics of MDMA, 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 4-hydroxy-3-methoxyamphetamine (HMA) and to test the effect of covariates like gender and body weight on the pharmacokinetics. Rats (18 males and 18 females) were given 1 mg/kg MDMA iv, and the concentrations of MDMA, MDA, and HMMA were measured by high-performance liquid chromatography-mass spectrometry. Another 30 rats (15 males) were given 1 mg/kg MDA, and MDA and HMA were measured. A population pharmacokinetic model was developed to describe the changes in MDMA, HMMA, MDA, and HMA concentrations over time and to estimate interanimal variability. The influence of gender was tested using a likelihood ratio test. Estimated exposures of males and females to MDMA and its metabolites were compared using the Wilcoxon nonparametric test. An integrated six-compartment model adequately described the data. MDMA (two compartments) was transformed irreversible to HMMA (one compartment) and MDA (two compartments), which then produced HMA (one compartment). All rate constants were first order. Females given MDMA had significantly smaller MDMA distribution volumes than males, and they converted less MDMA to MDA than did males. Our MDMA, MDA, HMA, and HMMA model is suitable for examining the relationship between drug concentrations and its pharmacological/toxicological effects. Male rats were exposed to significantly more MDA and HMA than were females, which could explain why males are more sensitive to MDMA toxic effects than females.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 4
- Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat Drug Metabolism and Disposition October 19, 2013
- Adolescent MDMA exposure diminishes the physiological and neurotoxic consequences of an MDMA binge in female rats Developmental Psychobiology July 1, 2014
- Sex Differences in Abuse-Related Neurochemical and Behavioral Effects of 3,4-methylenedioxymethamphetamine (MDMA) in Rats Pharmacology, Biochemistry, and Behavior August 24, 2016
- Gender differences in hyperthermia and regional 5-HT and 5-HIAA depletion in the brain following MDMA administration in rats. Brain Research May 4, 2011
Cites 16
- Differences Between the Mechanism of Action of MDMA, MBDB, and the Classic Hallucinogens. Identification of a New Therapeutic Class: Entactogens Journal of Psychoactive Drugs October 1, 1986
- Pharmacology of MDMA in Humans Annals of the New York Academy of Sciences September 1, 2000
- Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine After Controlled Oral Administration to Young Adults Therapeutic Drug Monitoring May 21, 2008
- Glutathione and N-Acetylcysteine Conjugates of α-Methyldopamine Produce Serotonergic Neurotoxicity: Possible Role in Methylenedioxyamphetamine-Mediated Neurotoxicity Chemical Research in Toxicology November 19, 1999
- Death rates from ecstasy (MDMA, MDA) and polydrug use in England and Wales 1996–2002 Human Psychopharmacology: Clinical and Experimental September 19, 2003
and 11 more in the library