Courtney Gearlds1, Jessica Brooke Bouldin1, Mariah McKinney1, Shannon Schreiner1, Stacy D Brown1, Brooks B Pond2. 1. Department of Pharmaceutical Sciences, East Tennessee State University Bill Gatton College of Pharmacy, Box 70594, Johnson City, TN, 37614, USA. 2. Department of Pharmaceutical Sciences, East Tennessee State University Bill Gatton College of Pharmacy, Box 70594, Johnson City, TN, 37614, USA. pond@etsu.edu.
Abstract
BACKGROUND AND OBJECTIVES: Approximately 10 years ago, "bath salts" became popular as legal alternatives to the psychostimulants cocaine and the amphetamines. These products contained synthetic cathinones, including 3,4-methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4-methylenedioxymethcathinone (methylone). Most preclinical investigations have only assessed the effects of these synthetic cathinones independently; however, case reports and Drug Enforcement Administration (DEA) studies indicate that bath salts contain mixtures of these substances. In this study, we examine the pharmacokinetic interactions of the drug combination. We hypothesized that combined exposure to MDPV, mephedrone, and methylone would result in increased drug concentrations and enhanced total drug concentrations when compared to individual administration. METHODS: Adolescent male Swiss-Webster mice were injected intraperitoneally with either 10 mg/kg MDPV, 10 mg/kg mephedrone, 10 mg/kg methylone, or 10 mg/kg combined MDPV, mephedrone, and methylone. Following injection, brains and plasma were collected at 1, 10, 15, 30, 60, and 120 min. Drugs were extracted via solid-phase extraction, and concentrations were determined using a previously published high-pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. RESULTS: All drugs crossed the blood-brain barrier quickly. For methylone, the maximal concentration (Cmax) and the total drug exposure [as represented by the area under the concentration-time curve (AUC)] were significantly higher when combined with mephedrone and MDPV in both matrices (2.89-fold increase for both Cmax and AUC with combined treatment). For mephedrone, the Cmax was unchanged, but the AUC in brain was increased when in combination by approximately 34%. Interestingly, for MDPV, the Cmax was unchanged, yet the AUC was higher when MDPV was administered individually (there was a 62% decrease in AUC with combined treatment). CONCLUSIONS: The pharmacokinetics of methylone, mepedrone, and MDPV are altered when the drugs are used in combination. These data provide insight into the consequences of co-exposure to synthetic cathinones in popular bath salt products.
BACKGROUND AND OBJECTIVES: Approximately 10 years ago, "bath salts" became popular as legal alternatives to the psychostimulants cocaine and the amphetamines. These products contained synthetic cathinones, including 3,4-methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4-methylenedioxymethcathinone (methylone). Most preclinical investigations have only assessed the effects of these synthetic cathinones independently; however, case reports and Drug Enforcement Administration (DEA) studies indicate that bath salts contain mixtures of these substances. In this study, we examine the pharmacokinetic interactions of the drug combination. We hypothesized that combined exposure to MDPV, mephedrone, and methylone would result in increased drug concentrations and enhanced total drug concentrations when compared to individual administration. METHODS: Adolescent male Swiss-Webster mice were injected intraperitoneally with either 10 mg/kg MDPV, 10 mg/kg mephedrone, 10 mg/kg methylone, or 10 mg/kg combined MDPV, mephedrone, and methylone. Following injection, brains and plasma were collected at 1, 10, 15, 30, 60, and 120 min. Drugs were extracted via solid-phase extraction, and concentrations were determined using a previously published high-pressure liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. RESULTS: All drugs crossed the blood-brain barrier quickly. For methylone, the maximal concentration (Cmax) and the total drug exposure [as represented by the area under the concentration-time curve (AUC)] were significantly higher when combined with mephedrone and MDPV in both matrices (2.89-fold increase for both Cmax and AUC with combined treatment). For mephedrone, the Cmax was unchanged, but the AUC in brain was increased when in combination by approximately 34%. Interestingly, for MDPV, the Cmax was unchanged, yet the AUC was higher when MDPV was administered individually (there was a 62% decrease in AUC with combined treatment). CONCLUSIONS: The pharmacokinetics of methylone, mepedrone, and MDPV are altered when the drugs are used in combination. These data provide insight into the consequences of co-exposure to synthetic cathinones in popular bath salt products.
Authors: Mariana Angoa-Pérez; Michael J Kane; Dina M Francescutti; Katherine E Sykes; Mrudang M Shah; Abiy M Mohammed; David M Thomas; Donald M Kuhn Journal: J Neurochem Date: 2012-02-09 Impact factor: 5.372
Authors: Michael H Baumann; John S Partilla; Kurt R Lehner; Eric B Thorndike; Alexander F Hoffman; Marion Holy; Richard B Rothman; Steven R Goldberg; Carl R Lupica; Harald H Sitte; Simon D Brandt; Srihari R Tella; Nicholas V Cozzi; Charles W Schindler Journal: Neuropsychopharmacology Date: 2012-10-17 Impact factor: 7.853
Authors: Joshua S Elmore; Ora Dillon-Carter; John S Partilla; Kayla N Ellefsen; Marta Concheiro; Masaki Suzuki; Kenner C Rice; Marilyn A Huestis; Michael H Baumann Journal: Neuropsychopharmacology Date: 2016-09-23 Impact factor: 7.853
Authors: Louise Karlsson; Mikael Andersson; Robert Kronstrand; Fredrik C Kugelberg Journal: Basic Clin Pharmacol Toxicol Date: 2014-05-06 Impact factor: 4.080
Authors: Klára Šíchová; Nikola Pinterová; Monika Židková; Rachel R Horsley; Eva Lhotková; Kristýna Štefková; Čestmír Vejmola; Libor Uttl; Marie Balíková; Martin Kuchař; Tomáš Páleníček Journal: Front Psychiatry Date: 2018-01-10 Impact factor: 4.157