M. Carbó

Clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"): the influence of gender and genetics (CYP2D6, COMT, 5-HTT)

The synthetic psychostimulant MDMA (±3,4-methylenedioxymethamphetamine, ecstasy) acts as an indirect serotonin, dopamine, and norepinephrine agonist and as a mechanism-based inhibitor of the cytochrome P-450 2D6 (CYP2D6). It has been suggested that women are more sensitive to MDMA effects than men but no clinical experimental studies have satisfactorily evaluated the factors contributing to such observations. There are no studies evaluating the influence of genetic polymorphism on the pharmacokinetics (CYP2D6; catechol-O-methyltransferase, COMT) and pharmacological effects of MDMA (serotonin transporter, 5-HTT; COMT). This clinical study was designed to evaluate the pharmacokinetics and physiological and subjective effects of MDMA considering gender and the genetic polymorphisms of CYP2D6, COMT, and 5-HTT. A total of 27 (12 women) healthy, recreational users of ecstasy were included (all extensive metabolizers for CYP2D6). A single oral weight-adjusted dose of MDMA was administered (1.4 mg/kg, range 75–100 mg) which was similar to recreational doses. None of the women were taking oral contraceptives and the experimental session was performed during the early follicular phase of their menstrual cycle. Principal findings show that subjects reached similar MDMA plasma concentrations, and experienced similar positive effects, irrespective of gender or CYP2D6 (not taking into consideration poor or ultra-rapid metabolizers) or COMT genotypes. However, HMMA plasma concentrations were linked to CYP2D6 genotype (higher with two functional alleles). Female subjects displayed more intense physiological (heart rate, and oral temperature) and negative effects (dizziness, sedation, depression, and psychotic symptoms). Genotypes of COMT val158met or 5-HTTLPR with high functionality (val/val or l/*) determined greater cardiovascular effects, and with low functionality (met/* or s/s) negative subjective effects (dizziness, anxiety, sedation). In conclusion, the contribution of MDMA pharmacokinetics following 1.4 mg/kg MDMA to the gender differences observed in drug effects appears to be negligible or even null. In contrast, 5-HTTLPR and COMT val158met genotypes play a major role. Trial Registration ClinicalTrials.gov NCT01447472

Automatic determination of MEP patterns of molecules and its application to caffeine metabolism inhibitors

Abstract Software has been developed to locate and determine accurately all the Molecular Electrostatic Potential (MEP) minima of a molecule and to plot the MEP maps corresponding to planes containing any three desired points (minima, atoms or dummy points). The minima description can be used as parameters in QSAR. Some of these techniques are used in the analysis of substances which inhibit caffeine metabolism and other similar, but inactive, compounds. The goal is to find electrostatic requirements associated with this inhibitory activity.

Concentrations of MDPV in rat striatum correlate with the psychostimulant effect

3,4-methylenedioxypyrovalerone or MDPV is a synthetic cathinone with psychostimulant properties more potent than cocaine. We quantified this drug in the striatum after subcutaneous administration to rats. MDPV reached the brain around 5 min after its administration and peaked at 20–25 min later. The elimination half-life in the striatum (61 min) correlates with the decrease in the psychostimulant effect after 60 min. Around 11% of the administered dose reached the striatum and, considering a homogeneous brain distribution, we determined that around 86% of the plasma MDPV is distributed to the brain. MDPV induced a dose-dependent increase in locomotor activity, rearing behaviour and stereotypies, all prevented by haloperidol. A plot of locomotor activity or stereotypies versus MDPV striatal concentrations over time showed a direct relationship between factors. No free MDPV metabolites were detected in plasma, at any time, but hydrolysis with glucuronidase allowed us to identify mainly three metabolites, one of them for the first time in rat plasma. The present results contribute to evidence that MDPV induces hyperlocomotion mainly through a dopamine-dependent mechanism. Good correlation between behavioural effects and striatal levels of MDPV leads us to conclude that its psychostimulant effect is mainly due to a striatal distribution of the substance. The present research provides useful information on the pharmacokinetics of MDPV, and can help design new experiments with kinetics data as well as provide a better understanding of the effects of MDPV in humans and its potential interactions.

Sex Differences in 3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy)-Induced Cytochrome P450 2D6 Inhibition in Humans

AbstractBackground and Objective: 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is a ring-substituted amphetamine widely used for recreational purposes. MDMA is predominantly O-demethylenated in humans by cytochrome P450 (CYP) 2D6 and is also a potent mechanism-based inhibitor of the enzyme. This study assessed the inhibition and recovery half-life of CYP2D6 and CYP3A4 activity in female subjects by administering the probe drug dextromethorphan before and repeatedly after MDMA administration. These data were compared with the data obtained from a previous study in male subjects. Study Design: Twelve healthy female subjects who were CYP2D6 extensive metabolizers participated as outpatients in two experimental sessions. Session 1 was conducted over 2 days and session 2 over 10 days, with a minimum of 3 days between sessions. In session 1, subjects received a single oral dose of dextromethorphan 30 mg. In session 2, a 1.5mg/kg MDMA dose was given at 0 hours, followed at 4 hours by repeated 30 mg doses of dextromethorphan over the next 10 days. Methods: Plasma concentration-time profiles and urinary recoveries of dextromethorphan and its metabolites dextrorphan (DOR), 3-methoxymorphinan (MM) and hydroxymorphinan-3-ol (HM) were measured. Results: MDMA given prior to dextromethorphan resulted in a 10-fold increase in the dextromethorphan maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC), with corresponding decreases in DOR and HM pharmacokinetic parameters. The mean ± SD Cmax of MDMA was 188.8 ± 16.7 ng/mL, with a time to reach Cmax (tmax) of 2.0±0.4 hours and an AUC from 0 to 25 hours of 2645.2±170.9 mg · h/mL. The urinary recovery of the dextromethorphan dose as dextromethorphan and its main metabolites was 25.4 ± 8.9% with no MDMA pretreatment versus 6.6±1.1% after 1.5mg/kg of MDMA (p = 0.0001). The metabolic ratio (MR) increased almost 60-fold from 0.018 ± 0.028 to 0.998±0.932 after MDMA administration, with 100% of the subjects having a value greater than the antimode of 0.3 that signified the poor-metabolizer phenotype. Data analysis of results obtained in the present study compared with those from a previous study in male subjects showed significant differences in the dextromethorphan/DOR MR in the 0- to 8-hour (session 1) and 4- to 12-hour (session 2, post MDMA) collection periods (p = 0.032 and p = 0.01, respectively). CYP2D6 activity recovered after 10 days to 90% of baseline activity, with a recovery half-life of 36.6 ± 22.9 hours. Male subjects showed a shorter recovery half-life (27.6 ± 25.1 hours). The measurement of CYP3A4 activity indicated a non-significant increase in Cmax and AUC values of MM after drug intake, but urinary data reflected significant differences in dextromethorphan/MM MR in both sexes, although the difference was more pronounced in women. Dextromethorphan/MM MR increased almost 3-fold from baseline. Discussion and Conclusion: resulted in a decrease in a decrease in dextromethorphan clearance. CYP2D6 activity recovered after 10 days to 90% of baseline activity. Regarding CYP3A4 activity, there is an apparent decrease in its activity after MDMA use. In women, MDMA use has been associated with psychiatric symptoms and psychological problems that may require psycho-pharmacological treatment with antidepressant drugs, some of which are known CYP2D6 substrates. MDMA-induced mechanism-based inhibition of CYP2D6 is of relevance, and physicians should be advised to prescribe medications whose metabolic disposition is not regulated by CYP2D6.

Pharmacokinetic determination of relative potency of quinolone inhibition of caffeine disposition

SummaryQuinolone is reported to interact with caffeine, often resulting in an increase both in the plasma half-life and AUC, a decrease in total plasma clearance, and little change in the absorption rate constant and maximum plasma level. These complex changes in the pharmacokinetics of caffeine were analyzed experimentally and from published reports in order to determine the nature of the interaction, which is thought to be due to inhibition of caffeine metabolism by quinolones.A simple pharmacokinetic model for the caffeine-quinolone interaction was developed, which provides a unified method for evaluation and comparison of the effect of quinolones on the disposition of caffeine.The model is applicable to other methylxanthines, such as theophylline. The relative potency of the interactions of quinolones with caffeine in humans has been established as enoxacin (100), pipemidic acid (29), ciprofloxacin (11), norfloxacin (9) and ofloxacin (0).