| Summary: | Approximately 10 years ago, “bath salts” were popularized as legal alternatives to the psychostimulants cocaine and the amphetamines, circumventing legislation with packages marked, “not for human consumption.” These products contained synthetic cathinones including 3,4-methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4-methylenedioxymethcathinone (methylone). The synthetic cathinones have similar pharmacology to controlled psychostimulants, increasing levels of dopamine (DA) in the synaptic cleft, while also exhibiting similar psychoactive effects such as increased energy and euphoria. Additionally, adverse effects of “bath salts” are similar to controlled psychostimulants, such as chest pain, shortness of breath, and hallucinations. Most preclinical investigations have only assessed the effects of these synthetic cathinones independently; however, case reports and DEA studies indicate that “bath salts” contain mixtures of these substances. Therefore, in a recent study by our laboratory, we examined effects of individual versus combined exposure to MDPV, mephedrone, and methylone. Interestingly, an enhanced effect on the levels of DA in a number of brain regions was observed, as well as significant alterations in locomotor activity following co-exposure to the cathinones. Here, we examine if the enhanced effects of the drug combination are due to pharmacokinetic (PK) interactions. Many of the same cytochrome isoenzymes metabolize each of these 3 drugs; thus, it is probable that the drugs’ PK would differ when administered individually as compared to in combination. We hypothesized that combined exposure to MDPV, mephedrone, and methylone would result in increased total drug concentrations when compared to individual administration. Briefly, 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 the following time points: 1, 10, 15, 30, 60, and 120 minutes. Drugs were extracted via solid-phase extraction, and concentrations were determined using a previously published high pressure-liquid chromatography tandem mass spectrometry method. All drugs quickly crossed the blood-brain barrier and entered the brain. PK data for methylone and mephedrone was consistent with our hypothesis. For methylone, the maximal concentration (Cmax) and the total drug exposure (as represented by the area under the curve (AUC)) were significantly higher when combined with mephedrone and MDPV in both matrices. For mephedrone, the Cmax was unchanged, but AUC in brain was increased when combined with the other two drugs. However, interestingly, for MDPV, the Cmax was unchanged, yet the AUC in brain was higher when MDPV was administered individually. These data provide insight into the consequences of co-exposure to synthetic cathinones in popular “bath salt” products.
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