P‐glycoprotein modulation by the designer drugs methylenedioxymethamphetamine, methylenedioxyethylamphetamine and paramethoxyamphetamine
Nahal Ketabi‐Kiyanvash, Johanna Weiss, Walter Emil Haefeli, Gerd Mikus
Addiction Biology December 1, 2003 DOI: 10.1080/13556210310001646475 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro laboratory study Peer reviewed |
|---|---|
| Population | Porcine kidney epithelial cells overexpressing human P-glycoprotein (L-MDR1) |
| Interventions | MDMA MDE PMA |
| Measures | fluorometric calcein assay |
| Topics | MDMA |
| Key points | MDMA, MDE, and PMA all increased calcein retention in Pgp-overexpressing cells in a concentration-dependent manner, with MDE the most potent and MDMA the weakest inhibitor. Effective concentrations were 1–3 orders of magnitude higher than in vivo plasma concentrations, suggesting these compounds are only weak Pgp inhibitors unlikely to influence other compounds' access to the brain. The authors caution that co-administration of Pgp inhibitors such as ritonavir or paroxetine could still increase bioavailability and brain entry of these compounds. |
Abstract
Abstract: There are increasing numbers of deaths related to taking MDMA, MDE and PMA reported where the deceased typically took several different drugs with these compounds. Hence, mutual modulation of the pharmacokinetics in drug combinations with “ecstasy” might be a risk factor for “ecstasy”‐related morbidity. Regarding potential drug‐drug interactions, there are no data evaluating a possible contribution of the multidrug resistance transporter P‐glycoprotein (Pgp) in contrast to the cytochrome P450 enzyme system. Therefore, individual “ecstasy” compounds have been tested for their ability to interact with Pgp using a fluorometric calcein assay as a model for Pgp inhibition in porcine kidney epithelial cells with overexpression of human Pgp (L‐MDR1). All three compounds increased calcein retention in L‐MDR1 cells in a concentration‐dependent manner, with MDE being the most potent and MDMA the weakest Pgp inhibitor. The effective concentrations were 1–3 orders of magnitude higher than plasma concentrations observed in vivo, suggesting that these compounds are only weak inhibitors of Pgp, which is unlikely to influence the access of other compounds to the brain. However, it cannot be excluded that co‐administration of Pgp inhibitors such as ritonavir or paroxetine could increase MDMA, MDE and PMA bioavailability and also enhance brain entry leading to severe side effects.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 3
- ( )-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
- Mice lacking multidrug resistance protein 1a show altered dopaminergic responses to methylenedioxymethamphetamine (MDMA) in striatum. Neurotoxicity Research October 23, 2009
- Fluoxetine pretreatment effects pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA, ECSTASY) in rat. Journal of Pharmaceutical Sciences April 2008
Cites 8
- Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings The Lancet October 1, 1998
- Toxicokinetics of Amphetamines: Metabolism and Toxicokinetic Data of Designer Drugs, Amphetamine, Methamphetamine, and Their N-Alkyl Derivatives Therapeutic Drug Monitoring April 1, 2002
- Fatal multi-organ failure after suicidal overdose with MDMA, `Ecstasy': case report and review of the literature Human & Experimental Toxicology February 1, 1999
- Differential toxic effects of methamphetamine (METH) and methylenedioxymethamphetamine (MDMA) in multidrug-resistant (mdr1a) knockout mice Brain Research September 1, 1997
- Ecstasy (MDMA): effects and patterns of use reported by users in São Paulo. Revista Brasileira de Psiquiatria March 2003
and 3 more in the library