Document Detail


Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug-drug interactions.
MedLine Citation:
PMID:  23030234     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Clinical outcome following 3,4-methylenedioxymethamphetamine (MDMA) intake ranges from mild entactogenic effects to a life-threatening intoxication. Despite ongoing research, the clinically most relevant mechanisms causing acute MDMA-induced adverse effects remain largely unclear. This complicates the triage and treatment of MDMA users needing medical care. The user's genetic profile and interactions resulting from polydrug use are key factors that modulate the individual response to MDMA and influence MDMA pharmacokinetics and dynamics, and thus clinical outcome. Polymorphisms in CYP2D6, resulting in poor metabolism status, as well as co-exposure of MDMA with specific substances (e.g. selective serotonin reuptake inhibitors (SSRIs)) can increase MDMA plasma levels, but can also decrease the formation of toxic metabolites and subsequent cellular damage. While pre-exposure to e.g. SSRIs can increase MDMA plasma levels, clinical effects (e.g. blood pressure, heart rate, body temperature) can be reduced, possibly due to a pharmacodynamic interaction at the serotonin reuptake transporter (SERT). Pretreatment with inhibitors of the dopamine or norepinephrine reuptake transporter (DAT or NET), 5-HT(2A) or α-β adrenergic receptor antagonists or antipsychotics prior to MDMA exposure can also decrease one or more MDMA-induced physiological and/or subjective effects. Carvedilol, ketanserin and haloperidol can reduce multiple MDMA-induced clinical and neurotoxic effects. Thus besides supportive care, i.e. sedation using benzodiazepines, intravenous hydration, aggressive cooling and correction of electrolytes, it is worthwhile to investigate the usefulness of carvedilol, ketanserin and haloperidol in the treatment of MDMA-intoxicated patients.
Authors:
Saskia J Rietjens; Laura Hondebrink; Remco H S Westerink; Jan Meulenbelt
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Publication Detail:
Type:  Journal Article; Review     Date:  2012-10-03
Journal Detail:
Title:  Critical reviews in toxicology     Volume:  42     ISSN:  1547-6898     ISO Abbreviation:  Crit. Rev. Toxicol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-12     Completed Date:  2013-03-20     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  8914275     Medline TA:  Crit Rev Toxicol     Country:  England    
Other Details:
Languages:  eng     Pagination:  854-76     Citation Subset:  IM    
Affiliation:
University Medical Center Utrecht, Division of Anesthesiology, Intensive Care and Emergency Medicine, National Poisons Information Center (NVIC), P.O. box 85500, 3508 GA, Utrecht, The Netherlands. S.Rietjens@umcutrecht.nl
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Pressure / drug effects
Body Temperature / drug effects
Brain / drug effects,  metabolism
Carbazoles / pharmacokinetics,  pharmacology
Cytochrome P-450 CYP2D6 / genetics
Drug Interactions
Glutathione Transferase / genetics
Haloperidol / pharmacokinetics,  pharmacology
Heart Rate / drug effects
Humans
Ketanserin / pharmacokinetics,  pharmacology
Models, Animal
N-Methyl-3,4-methylenedioxyamphetamine / blood,  pharmacokinetics*,  pharmacology*
Neurotransmitter Transport Proteins / genetics
Polymorphism, Genetic*
Propanolamines / pharmacokinetics,  pharmacology
Receptors, Neurotransmitter / metabolism
Serotonin Syndrome / chemically induced,  physiopathology
Serotonin Uptake Inhibitors / pharmacokinetics,  pharmacology
Chemical
Reg. No./Substance:
0/Carbazoles; 0/Neurotransmitter Transport Proteins; 0/Propanolamines; 0/Receptors, Neurotransmitter; 0/Serotonin Uptake Inhibitors; 0K47UL67F2/carvedilol; 42542-10-9/N-Methyl-3,4-methylenedioxyamphetamine; 52-86-8/Haloperidol; 74050-98-9/Ketanserin; EC 1.14.14.1/Cytochrome P-450 CYP2D6; EC 2.5.1.18/Glutathione Transferase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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