Department of Pharmaceutical Sciences, Mercer University College of Pharmacy, Mercer University Health Sciences Center, 3001 Mercer University Dr., Atlanta, GA, 30341, USA.
Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, Durham, NC, 27709, USA.
Drug Deliv Transl Res. 2020 Feb;10(1):271-281. doi: 10.1007/s13346-019-00685-4.
3-Fluoroamphetamine (also called PAL-353) is a synthetic amphetamine analog that has been investigated for cocaine use disorder (CUD), yet no studies have characterized its pharmacokinetics (PK). In the present study, we determined the PK of PAL-353 in male Sprague Dawley rats following intravenous bolus injection (5 mg/kg). Plasma samples were analyzed using a novel bioanalytical method that coupled liquid-liquid extraction and LC-MS/MS. The primary PK parameters determined by WinNonlin were a C (ng/mL) of 1412.09 ± 196.12 and a plasma half-life of 2.27 ± 0.67 h. As transdermal delivery may be an optimal approach to delivering PAL-353 for CUD, we assessed its PK profile following application of 50 mg of transdermal gel (10% w/w drug over 5 cm). The 10% w/w gel resulted in a short lag time, sustained delivery, and a rapid clearance in plasma immediately after removal. The rodent PK data were verified by examining in vitro permeation through human epidermis mounted on Franz diffusion cells. An in vitro-in vivo correlation (IVIVC) analysis was performed using the Phoenix IVIVC toolkit to assess the predictive relationship between rodent and human skin absorption/permeation. The in vitro permeation study revealed a dose-proportional cumulative and steady-state flux with ~ 70% of drug permeated. The fraction absorbed in vivo and fraction permeated in vitro showed a linear relationship. In conclusion, we have characterized the PK profile of PAL-353, demonstrated that it has favorable PK properties for transdermal administration for CUD, and provided preliminary evidence of the capacity of rodent data to predict human skin flux.
3-氟苯丙胺（也称为 PAL-353）是一种合成苯丙胺类似物，已被研究用于可卡因使用障碍（CUD），但尚无研究描述其药代动力学（PK）。在本研究中，我们在雄性 Sprague Dawley 大鼠中通过静脉推注（5mg/kg）确定了 PAL-353 的 PK。使用一种新的液液萃取和 LC-MS/MS 相结合的生物分析方法分析血浆样品。WinNonlin 确定的主要 PK 参数为 C（ng/mL）为 1412.09±196.12，血浆半衰期为 2.27±0.67h。由于透皮给药可能是为 CUD 递送 PAL-353 的最佳方法，我们评估了其在应用 50mg 透皮凝胶（10%w/w 药物超过 5cm）后的 PK 特征。10%w/w 凝胶导致短的滞后时间、持续的递送以及在去除后立即在血浆中快速清除。通过检查在 Franz 扩散细胞上安装的人表皮的体外渗透，验证了啮齿动物 PK 数据。使用 Phoenix IVIVC 工具包进行体外-体内相关性（IVIVC）分析，以评估啮齿动物和人皮肤吸收/渗透之间的预测关系。体外渗透研究显示剂量比例累积和稳态通量，有~70%的药物渗透。体内吸收分数和体外渗透分数呈线性关系。总之，我们已经描述了 PAL-353 的 PK 特征，证明它具有用于 CUD 的透皮给药的良好 PK 特性，并提供了啮齿动物数据预测人皮肤通量的初步证据。
