Impact of common clandestine structural modifications on synthetic cathinone "bath salt" pharmacokinetics

Since 2009, the synthetic cathinones ("bath salts") have risen in popularity as drugs of abuse. However, there are a paucity of studies that have determined the impact of functional group modifications in the synthetic cathinone chemical structures on plasma and central nervous system (CNS) pharmacokinetics. In the present study, we investigated the in vivo plasma and CNS pharmacokinetics of three synthetic cathinones whose structures differ by lengthening of the α-alkyl chain: methylone (-CH₃), butylone (-CH₂CH₃), and pentylone (-CH₂CH₂CH₃). Male Sprague-Dawley rats were treated with a 20mg/kg subcutaneous dose of the individual synthetic cathinone. Blood samples were obtained at specific times from a jugular vein cannula over an 8hour period. Over a separate three-hour period, CNS samples were obtained using a microdialysis cannula surgically implanted into the lateral ventricle. In the plasma, pentylone, with the longest α-alkyl chain, displayed the highest C_max and AUC_0-∞, and the longest t_1/2. Decreasing the α-alkyl chain length as in butylone and methylone significantly decreased the C_max, AUC_0-∞, and t_1/2. The plasma pharmacokinetic values are consistent with the greater lipophilicity associated with α-alkyl side chain lengthening. Conversely, in the CNS, methylone and butylone displayed higher C_max and AUC_0-∞ values than pentylone. These contrary findings in the CNS and plasma demonstrate that lengthening of the α-alkyl chain of methylone, butylone, and pentylone yields differential pharmacokinetic properties in the CNS as compared to the plasma.