Mireia Segura

γ‐Hydroxybutyrate (GHB) in Humans

Abstract:  Despite γ‐hydroxybutyrate (GHB) therapeutic uses and the increasing concern about its toxicity, few studies have addressed GHB dose‐related effects under controlled administration and their relationship with its pharmacokinetics. The study design was double‐blind, randomized, crossover, and controlled. As a pilot pharmacology phase I study, increasing doses of GHB were given. Single oral sodium GHB doses (40, 50, 60, and 72 mg/kg) were administered to eight volunteers. Plasma and urine were analyzed for GHB by gas chromatography–mass spectrometry. Physiological effects, psychomotor performance, and subjective effects were examined simultaneously. GHB produced dose‐related changes in subjective effects as measured by questionnaires and VAS. GHB showed a mixed stimulant‐sedative pattern, with initially increased scores in subjective feeling of euphoria, high, and liking followed by mild‐moderate symptoms of sedation with impairment of performance and balance. Mean peak GHB plasma concentrations were 79.1, 83.1, 113.5, and 130.1 μg/L for 40, 50, 60, and 72 mg/kg, respectively. GHB‐mediated physiological and subjective effects were dose dependent and related to GHB plasma concentrations. GHB urinary excretion was mainly related to administered doses. GHB‐mediated subjective and physiological effects seem dose dependent and related to GHB plasma concentrations. Results suggest a high abuse liability of GHB in the range of dose usually consumed.

A comparative study on the acute and long‐term effects of MDMA and 3,4‐dihydroxymethamphetamine (HHMA) on brain monoamine levels after i.p. or striatal administration in mice

1 This study investigated whether the immediate and long‐term effects of 3,4‐methylenedioxymethamphetamine (MDMA) on monoamines in mouse brain are due to the parent compound and the possible contribution of a major reactive metabolite, 3,4‐dihydroxymethamphetamine (HHMA), to these changes. The acute effect of each compound on rectal temperature was also determined. 2 MDMA given i.p. (30 mg kg−1, three times at 3‐h intervals), but not into the striatum (1, 10 and 100 μg, three times at 3‐h intervals), produced a reduction in striatal dopamine content and modest 5‐HT reduction 1 h after the last dose. MDMA does not therefore appear to be responsible for the acute monoamine release that follows its peripheral injection. 3 HHMA does not contribute to the acute MDMA‐induced dopamine depletion as the acute central effects of MDMA and HHMA differed following i.p. injection. Both compounds induced hyperthermia, confirming that the acute dopamine depletion is not responsible for the temperature changes. 4 Peripheral administration of MDMA produced dopamine depletion 7 days later. Intrastriatal MDMA administration only produced a long‐term loss of dopamine at much higher concentrations than those reached after the i.p. dose and therefore bears little relevance to the neurotoxicity. This indicates that the long‐term effect is not attributable to the parent compound. HHMA also appeared not to be responsible as i.p. administration failed to alter the striatal dopamine concentration 7 days later. 5 HHMA was detected in plasma, but not in brain, following MDMA (i.p.), but it can cross the blood–brain barrier as it was detected in the brain following its peripheral injection. 6 The fact that the acute changes induced by i.p. or intrastriatal HHMA administration differed indicates that HHMA is metabolised to other compounds which are responsible for changes observed after i.p. administration.

Pharmacological Interaction between 3,4-Methylenedioxymethamphetamine (Ecstasy) and Paroxetine: Pharmacological Effects and Pharmacokinetics

3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) is increasingly used by young people for its euphoric and empathic effects. MDMA can be used in combination with other drugs such as selective serotonin reuptake inhibitors. A clinical trial was designed where subjects pretreated with paroxetine, one of the most potent inhibitors of both 5-hydroxytryptamine reuptake and CYP2D6 activity, were challenged with a single dose of MDMA. The aim of the study was to evaluate the pharmacodynamic and pharmacokinetic interaction between paroxetine and MDMA in humans. A randomized, double-blind, crossover, placebo-controlled trial was conducted in 12 healthy male subjects. Variables included physiological parameters, psychomotor performance, subjective effects, and pharmacokinetics. Subjects received 20 mg/day paroxetine (or placebo) orally for the 3 days before MDMA challenge (100 mg oral). MDMA alone produced the prototypical effects of the drug. Pretreatment with paroxetine was associated with marked decreases of both physiological and subjective effects of MDMA, despite a 30% increase in MDMA plasma concentrations. The decreases of 3-methoxy-4-hydroxymethamphetamine plasma concentrations suggest a metabolic interaction of paroxetine and MDMA. These data show that pretreatment with paroxetine significantly attenuates MDMA-related physiological and psychological effects. It seems that paroxetine could interact with MDMA at pharmacodynamic (serotonin transporter) and pharmacokinetic (CYP2D6 metabolism) levels. Marked decrease in the effects of MDMA could lead users to take higher doses of MDMA and to produce potential life-threatening toxic effects.

Contribution of cytochrome P450 2D6 to 3,4- methylenedioxymethamphetamine disposition in humans : Use of paroxetine as a metabolic inhibitor probe

AbstractBackground: 3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine derivative typically used for recreational purposes. The participation of cytochrome P450 (CYP) 2D6 in the oxidative metabolism of MDMA may suggest an increased risk of acute toxicity in CYP2D6 poor metabolisers. This study was aimed at assessing the contribution of CYP2D6 to MDMA disposition in vivo using paroxetine as a metabolic probe inhibitor. Paroxetine, a CYP2D6 inhibitor, was repeatedly administered before MDMA administration. Study design: This was a randomised, double-blind, crossover, placebo-controlled trial conducted in seven healthy male volunteers who were CYP2D6 extensive metabolisers. Treatment conditions (paroxetine/MDMA and placebo/ MDMA) were randomly assigned. Each volunteer participated in two 3-day sessions. On days 1, 2 and 3 subjects received a single oral dose of paroxetine or placebo 20mg. On the third day, a single oral dose of MDMA 100mg was administered in both paroxetine and placebo conditions. Methods: Plasma concentration-time profiles and urinary recoveries of MDMA and its metabolites were measured, as well as plasma concentrations of paroxetine, (3S,4R)-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)-piperidine, and (3S,4R)-4-(4-fluorophenyl)-3-(3-methoxy-4-hydroxyphenoxymethyl)-piperidine (HM-paroxetine). Results: Paroxetine given before MDMA resulted in significant increases of MDMA area under the plasma concentration-time curve from 0 to 27 hours (AUC27) [23%], AUC from zero to infinity (AUC∞) [27%] and maximum plasma concentration (Cmax) [17%], without significant differences in MDMA time to reach Cmax (tmax). MDMA elimination-related pharmacokinetic parameters showed a significant reduction of MDMA elimination rate constant (Ke) [−14%] and plasmatic clearance (CLP) [−29%]. In the case of 3,4-dihydroxymethamphetamine (HHMA), a 21% decrease in Cmax with no significant differences in AUC27, AUC∞, Ke and elimination half-life) were found. 4-Hydroxy-3-methoxymethamphetamine (HMMA) showed a decrease in plasma concentrations with a reduction in AUC27 (−28%), AUC∞ (−20%) and Cmax (−46%). In the case of 3,4-methylenedioxyamphetamine (MDA) an increase in Cmax (17%) and AUC27 (16%) was found. Following paroxetine pretreatment, the urinary recovery (0–45 hours) of MDMA increased by 11%; HHMA and HMMA urinary recoveries were 27% and 16% lower, respectively compared with placebo. The ratio of Cmax values of paroxetine and its metabolite on days 1 and 3 showed a 3-fold reduction, with no differences in tmax. Discussion and conclusion: The contribution of CYP2D6 to MDMA metabolism in humans is not >30%, therefore other CYP isoenzymes may contribute to O-demethylenation of MDMA. Accordingly, the relevance of genetic polymorphism in CYP2D6 activity on MDMA effects and MDMA-induced acute toxicity should be examined as well as the interactions of other CYP2D6 substrates with MDMA, once the enzyme is inhibited. The pharmacokinetics of HM-paroxetine in humans after the administration of repeated doses is reported for the first time in this study.

MDMA (ecstasy) pharmacokinetics in a CYP2D6 poor metaboliser and in nine CYP2D6 extensive metabolisers.

(CYP)isoform 2D6 [2]. HHMA is further metabolised to 4-hydroxy, 3-methoxymethamphetamine (HMMA) bycatechol- O-methyltransferase (COMT). HMMA in-duces vasopressin secretion to a higher extent thanMDMA and has been postulated to contribute to hyp-onatraemia observed in some MDMA acute intoxica-tions [4]. The CYP2D6 gene is highly polymorphic andmany variations affect the expression or activity of theenzyme. Approximately 7–10% of European Caucasianspresent a metabolic deficiency and are termed poormetabolisers (PM) [12]. Evidence that individuals pos-sessingacompromiseinCYP2D6activitywouldbemoresusceptible to acute toxic effects of MDMA has beenlacking. A previous metabolic bioactivation of MDMA,regulated partially by this enzyme, is needed to elicitneurotoxic effects in the central nervous system. It ispostulated that the chemical species involved inserotonergic neurotoxicity are catechol thiol conjugatemetabolites of the drug (HHMA) [8]. The functionalpolymorphisms in CYP2D6 could influence the devel-opment of MDMA neurotoxicity. During a trial de-signed to study the pharmacology of two consecutivedoses of MDMA [3], one subject was found to possessthe CYP2D6*4/*4 genotype and was classified as a PM.The objective of this paper was to compare the results ofthis subject with those of nine others previously pub-lished. Furthermore, the paper includes pharmacokineticdata on MDMA metabolites not previously published.

Disposition of gamma-hydroxybutyric acid in conventional and nonconventional biologic fluids after single drug administration: issues in methodology and drug monitoring.

Little controlled drug administration data are available to aid in the interpretation of gamma-hydroxybutyric acid (GHB) distribution in conventional and nonconventional fluids and the potential correlation between the pharmacokinetics of GHB and drug effects. Single oral sodium GHB doses of 50 mg/kg were administered to five volunteers. Plasma, oral fluid, urine, and sweat were analyzed for GHB by gas chromatography-mass spectrometry. GHB stability in plasma was studied at different storage temperatures. Subjective effects were measured using a set of 13 different visual analog scales. Mean peak GHB plasma concentrations at 30 minutes were 83.1 μg/mL. After the absorption phase, concentrations declined to mean values of 0.9 μg/mL at 6 hours. GHB was found in oral fluid at peak value concentrations equivalent to one third to one fourth of those found in plasma. The oral fluid-to-plasma ratio varied two fold in the 1- to 6-hour time range but always was lower than unit. The mean half-life (t1/2) of GHB was approximately 0.7 hour in plasma and approximately 1.2 hours in oral fluid. GHB urinary excretion is less than 2% of the dose administered. GHB was also detected in sweat at low concentrations. GHB showed a mixed sedative-stimulant pattern with subjective effects peaking between 1 and 1.5 hours after drug administration and lasting for 2 hours. Oral fluid and sweat appeared not to be suitable biologic matrices for monitoring GHB consumption. GHB -mediated subjective effects are related to GHB plasma concentrations.

Synthesis of the major metabolites of Paroxetine

Paroxetine is a well-known antidepressant, used worldwide in therapeutics. In comparison with other selective serotonin reuptake inhibitors, it exhibits the highest activity in serotonin reuptake inhibition. Paroxetine metabolism initially involves its demethylenation to the catechol intermediate, which is then O-methylated at positions C3 or C4. Herein, the chemistry resulting in the syntheses of these metabolites (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine and (3S,4R)-4-(4-fluorophenyl)-3-(4-hydroxy-3-methoxyphenoxymethyl)piperidine is described starting from the common intermediate (3S,4R)-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. Additionally, the common intermediate was used to synthesize paroxetine, which had the same structure and stereochemistry as commercial paroxetine, thereby confirming our synthetic route.