Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2487499 | Journal of Pharmaceutical Sciences | 2008 | 13 Pages |
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 Pâglycoprotein (Pâgp) on mediating drug-drug interactions with MDMA. Biâdirectional transport studies were conducted across MDCKâMDR1 and Cacoâ2 monolayers. MDMA brain and plasma levels were measured in Pâgp deficient [mdr1a(â/â)] 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 Pâgp deficient versus normal mice. Pretreatment of rats with fluoxetine resulted in an increase in MDMA (1.4âfold) and MDA (1.5âfold) exposure in both brain and plasma. Elimination halfâlife was increased for MDMA (2.4 vs. 4.9 h) and MDA (1.8 vs. 8.2 h) with fluoxetine pretreatment. Pâgp 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. © 2007 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 97:1593-1605, 2008
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Authors
Vijay V. Upreti, Natalie D. Eddington,