Nadia Benturquia1, Lucie Chevillard1, Christophe Poiré1,2, Olivier Roussel1,3, Camille Cohier1,3, Xavier Declèves1, Jean-Louis Laplanche1, Mélanie Etheve-Quelquejeu2, Huixiong Chen2, Bruno Mégarbane4,5. 1. Inserm, UMR-S 1144, Paris-Descartes and Paris-Diderot Universities, Paris, France. 2. CNRS, UMR8601, Laboratory of Chemistry and Pharmacological and Toxicological Biochemistry, CBNIT, Paris-Descartes University, Paris, France. 3. Toxicology Department, Institut de Recherche Criminelle de la Gendarmerie Nationale, Rosny sous-Bois, France. 4. Inserm, UMR-S 1144, Paris-Descartes and Paris-Diderot Universities, Paris, France. bruno-megarbane@wanadoo.fr. 5. Department of Medical and Toxicological Critical Care, Lariboisière Hospital, Paris, France. bruno-megarbane@wanadoo.fr.
Abstract
RATIONALE: The use of synthetic cathinones as recreational drugs frequently sold in combination has been increasing exponentially. However, the consequences of combining cathinones on the resulting stimulant effects and the pharmacokinetics have been poorly investigated. OBJECTIVE AND METHODS: To study 3,4-methylenedioxypyrovalerone (MDPV; 3 mg/kg) and mephedrone (4-MMC; 30 mg/kg)-induced effects on rat locomotor activity and pharmacokinetics, administered alone or in combination by the intragastric route. The pharmacokinetic parameters were determined using non-compartmental analysis and the relationships between the locomotor activity and drug concentrations using sigmoidal Emax modeling. RESULTS: Locomotor activity significantly increased during the first hour post-administration with the MDPV/4-MMC combination in comparison to MDPV (p < 0.001) and 4-MMC (p < 0.01) alone. The pharmacokinetic profile of MDPV, but not 4-MMC, was significantly modified with the combination resulting in decreases in Cmax (16.4 ± 5.5 versus 62.2 ± 14.2 μg/L, p < 0.05) and AUC0 → ∞ (708 ± 91 versus 3316 ± 682 μg/L/min, p < 0.01) and increases in V/F (582.6 ± 136.8 versus 115.9 ± 42.7 L/kg, p < 0.05) and Cl/F (4.6 ± 0.7 versus 1.2 ± 0.4 L/kg/min, p < 0.01) in comparison to MDPV alone. The sigmoidal Emax model fitted the observed data well; MDPV being markedly more potent than 4-MMC (EC50, 0.043 versus 0.7 μmol/L). The enhancing factor representing the MDPV contribution to the alteration in the relationships between locomotor activity and 4-MMC concentrations was 0.3. CONCLUSION: An MDPV/4-MMC combination results in enhanced stimulant effects in the rat, despite significant reduction in MDPV bioavailability. Enhanced effects could be explained by increased MDPV distribution and/or possible complementation at the brain dopaminergic targets. However, the exact consequences of the MDPV/4-MMC combination in humans remain to be clarified.
RATIONALE: The use of synthetic cathinones as recreational drugs frequently sold in combination has been increasing exponentially. However, the consequences of combining cathinones on the resulting stimulant effects and the pharmacokinetics have been poorly investigated. OBJECTIVE AND METHODS: To study 3,4-methylenedioxypyrovalerone (MDPV; 3 mg/kg) and mephedrone (4-MMC; 30 mg/kg)-induced effects on rat locomotor activity and pharmacokinetics, administered alone or in combination by the intragastric route. The pharmacokinetic parameters were determined using non-compartmental analysis and the relationships between the locomotor activity and drug concentrations using sigmoidal Emax modeling. RESULTS: Locomotor activity significantly increased during the first hour post-administration with the MDPV/4-MMC combination in comparison to MDPV (p < 0.001) and 4-MMC (p < 0.01) alone. The pharmacokinetic profile of MDPV, but not 4-MMC, was significantly modified with the combination resulting in decreases in Cmax (16.4 ± 5.5 versus 62.2 ± 14.2 μg/L, p < 0.05) and AUC0 → ∞ (708 ± 91 versus 3316 ± 682 μg/L/min, p < 0.01) and increases in V/F (582.6 ± 136.8 versus 115.9 ± 42.7 L/kg, p < 0.05) and Cl/F (4.6 ± 0.7 versus 1.2 ± 0.4 L/kg/min, p < 0.01) in comparison to MDPV alone. The sigmoidal Emax model fitted the observed data well; MDPV being markedly more potent than 4-MMC (EC50, 0.043 versus 0.7 μmol/L). The enhancing factor representing the MDPV contribution to the alteration in the relationships between locomotor activity and 4-MMC concentrations was 0.3. CONCLUSION: An MDPV/4-MMC combination results in enhanced stimulant effects in the rat, despite significant reduction in MDPV bioavailability. Enhanced effects could be explained by increased MDPV distribution and/or possible complementation at the brain dopaminergic targets. However, the exact consequences of the MDPV/4-MMC combination in humans remain to be clarified.
Authors: Rosa A S Couto; Constantino Coelho; Bassim Mounssef; Sara F de A Morais; Camila D Lima; Wallans T P Dos Santos; Félix Carvalho; Cecília M P Rodrigues; Ataualpa A C Braga; Luís Moreira Gonçalves; M Beatriz Quinaz Journal: Nanomaterials (Basel) Date: 2021-02-01 Impact factor: 5.076