The inhalational administration of drugs is a practical and non‐invasive approach with the potential to reduce side effects and with a quick onset of therapeutic activity. Perillyl alcohol (POH) is a monoterpene with antitumor activity that currently is undergoing clinical evaluation as an inhalational anticancer agent. A detection method was developed that will be applicable to pharmacokinetic studies of not only POH, but also its longer‐lived main metabolite, perillic acid (PA), in lung tissue and plasma after inhalational delivery. The anticancer activity of POH was investigated in vitro with the use of various lung cancer cell lines. Toxicity was established by a standard MTT assay, and apoptosis markers were analyzed by Western blot. For the detection of POH and PA in lungs and plasma, albino Wistar rats were used that were exposed to POH inhalation. Tissues were subjected to chromatographic separation on an Agilent Zorbax Eclipse XDB C₁₈ column, followed by detection of absorption in the ultraviolet (UV) range. In vitro, POH exerted cytotoxic activity against six different lung tumor cell lines, and apoptotic cell death was indicated by induction of active caspase 3 and cleavage of poly (ADP‐ribose) polymerase 1 (PARP1). These results demonstrate that inhalational delivery of POH results in effective biodistribution and metabolism of POH in the systemic circulation. In addition, our study introduces a simple, rapid HPLC‐UV method with high accuracy for simultaneous detection of POH and its metabolite PA in plasma, and for sensitive detection of PA in lung tissue, which should prove useful for applications in clinical studies.

中文翻译：

---

Wistar大鼠吸入给药后血浆和肺中紫苏醇及其代谢产物紫苏酸的同时测定。

药物吸入是一种实用且无创的方法，具有减少副作用和快速起效的治疗作用。紫苏醇（POH）是一种具有抗肿瘤活性的单萜，目前正在作为吸入性抗癌剂进行临床评估。开发了一种检测方法，该方法不仅适用于POH的吸入动力学研究，而且还适用于肺组织和血浆中POH及其寿命更长的主要代谢产物紫苏酸（PA）的药代动力学研究。使用各种肺癌细胞系体外研究了POH的抗癌活性。通过标准MTT测定法确定毒性，并通过Western印迹分析凋亡标志物。为了检测肺和血浆中的POH和PA，使用暴露于POH吸入的白化Wistar大鼠。组织在Agilent Zorbax Eclipse XDB C上进行色谱分离₁₈柱，然后检测紫外线（UV）范围内的吸收。在体外，POH对六种不同的肺肿瘤细胞系具有细胞毒活性，诱导半胱天冬酶3的活化和多聚（ADP-核糖）聚合酶1（PARP1）的裂解表明细胞凋亡。这些结果表明，POH的吸入递送导致POH在全身循环中有效地生物分布和代谢。此外，我们的研究还引入了一种简单，快速，高精度的HPLC-UV方法，用于同时检测血浆中的POH及其代谢产物PA，以及灵敏地检测肺组织中的PA，这在临床研究中应被证明是有用的。