Fluoxetine pretreatment effects pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA, ECSTASY) in rat.
Vijay Upreti, Natalie D. Eddington
Journal of Pharmaceutical Sciences April 2008 DOI: 10.1002/jps.21045 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical pharmacokinetic drug-interaction study Peer reviewed |
|---|---|
| Population | MDCK-MDR1 and Caco-2 cell monolayers; P-gp deficient [mdr1a(-/-)] and normal [mdr1a(+/+)] mice; Sprague-Dawley rats |
| Interventions | MDMA Fluoxetine |
| Dose | MDMA 5 mg/kg i.p. (mice); MDMA 10 mg/kg p.o. (rats); fluoxetine 10 mg/kg i.p. for 4 days |
| Duration | Fluoxetine pretreatment 4 days; brain and plasma samples collected over 10 h after MDMA |
| Measures | HPLC method with fluorescence detection |
| Topics | MDMA |
| Key points | MDMA showed high, essentially unpolarized permeability, and brain MDMA and MDA levels did not differ between P-gp-deficient and normal mice, indicating P-gp has no physiologically relevant role in MDMA absorption or distribution. Fluoxetine pretreatment in rats increased MDMA exposure 1.4-fold and MDA 1.5-fold in brain and plasma and prolonged elimination half-lives (MDMA 2.4 to 4.9 h; MDA 1.8 to 8.2 h). The authors argue caution is needed when recommending fluoxetine to protect against MDMA-induced long-term neurotoxicity. |
Abstract
Fluoxetine has been shown to provide protection from MDMA induced long term neurotoxicity. The purpose of this investigation is to evaluate the pharmacokinetic drug interaction between MDMA and fluoxetine and also to determine the role of P-glycoprotein (P-gp) on mediating drug-drug interactions with MDMA. Bi-directional transport studies were conducted across MDCK-MDR1 and Caco-2 monolayers. MDMA brain and plasma levels were measured in P-gp deficient [mdr1a(-/-)] and normal [mdr1a(+/+)] mice after a 5 mg/kg i.p. dose of MDMA. Sprague-Dawley rats were pretreated with fluoxetine (4 days, 10 mg/kg, i.p.) or saline followed by MDMA (10 mg/kg, p.o.) and brain and plasma samples were collected over 10 h. MDMA and its active metabolite MDA were quantified using a HPLC method with fluorescence detection. In transport studies MDMA exhibited high permeability with essentially unpolarized transport. No significant difference in MDMA and MDA brain levels were seen in P-gp deficient versus normal mice. Pretreatment of rats with fluoxetine resulted in an increase in MDMA (1.4-fold) and MDA (1.5-fold) exposure in both brain and plasma. Elimination half-life was increased for MDMA (2.4 vs. 4.9 h) and MDA (1.8 vs. 8.2 h) with fluoxetine pretreatment. P-gp does not play a physiologically relevant role in absorption and distribution of MDMA, hence this transporter may not have a role in drug-drug interactions with MDMA. Fluoxetine pretreatment to provide protection from MDMA induced long term neurotoxicity decreases elimination of MDMA and MDA and may lead to enhanced risk of MDMA acute toxic effects. Overall, our results indicate that caution need to be practiced when recommending fluoxetine as an agent to provide protection from MDMA induced long term neurotoxicity.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 13
- Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug–drug interactions Critical Reviews in Toxicology October 3, 2012
- Nonlinear Pharmacokinetics of (±)3,4-Methylenedioxymethamphetamine (MDMA) and Its Pharmacodynamic Consequences in the Rat Drug Metabolism and Disposition October 19, 2013
- ( )-3,4-Methylenedioxymethamphetamine and Metabolite Disposition in Plasma and Striatum of Wild-Type and Multidrug Resistance Protein 1a Knock-Out Mice Journal of Analytical Toxicology September 1, 2011
- Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): Neurodegeneration versus Neuromodulation Pharmaceuticals July 5, 2011
- Neuronal Nicotinic Receptors as New Targets for Amphetamine-Induced Oxidative Damage and Neurotoxicity Pharmaceuticals June 15, 2011
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Cites 18
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- 'Eve' and 'Ecstasy' JAMA March 27, 1987
- MDMA (3,4-Methylenedioxymethamphetamine) or Ecstasy: The Neuropsychobiological Implications of Taking It at Dances and Raves Neuropsychobiology 2004
- The mechanisms involved in the long‐lasting neuroprotective effect of fluoxetine against MDMA (‘ecstasy’)‐induced degeneration of 5‐HT nerve endings in rat brain British Journal of Pharmacology September 1, 2001
- MDMA: A Review of Epidemiological Data Journal of Psychoactive Drugs June 1, 2002
and 13 more in the library