Perillyl alcohol (POH) is a monocyclic terpene that has strong antitumor activity. Brain tumors are particularly difficult to treat with therapeutic agents, and clinical trials have shown their low tolerance through oral administration. We proposed the entrapment of POH into an oil‐in‐water chitosan nanoemulsion aiming its intranasal administration for brain targeting. An ultra‐performance liquid chromatography/tandem mass spectrometry (UPLC–MS/MS) method was developed and validated for the quantitation of total metabolite perillic acid (PA) in plasma and brain of rats. The rat samples containing the metabolite were treated by liquid–liquid extraction with acetonitrile. The mobile phase was 0.1% formic acid in water (solvent A) and 0.1% formic acid in methanol (solvent B), at a flow rate of 0.3 mL min⁻¹ in gradient elution. The chromatography was run for 10 min, and analytical curves were built in acetonitrile, plasma, and brain. The PA was detected in positive ion mode with multiple reaction monitoring. The method has shown high selectivity, sensitivity, and throughput. The low quantification limits of 162, 178, and 121 ng mL⁻¹ for acetonitrile, brain, and plasma, respectively, indicate a good detectability of the method. The repeatability and precision observed were within the limits recommended in the literature. The accuracy of the method was verified through high recovery rates (106–118%). The validated method was successfully applied to the pharmacokinetic study of the metabolite PA after the intranasal administration of free or POH‐loaded nanoemulsion in rats. The results showed that chitosan nanoemulsion improved the plasma and brain bioavailability of POH, representing a promising alternative to free POH treatment.

中文翻译：

---

超高效液相色谱/串联质谱法在大鼠血浆和脑内鼻腔给药紫苏醇纳米乳的给药及其代谢产物紫苏酸的药代动力学研究

紫苏醇（POH）是单环萜烯，具有很强的抗肿瘤活性。脑肿瘤特别难以用治疗剂治疗，临床试验表明，口服给药对脑肿瘤的耐受性低。我们提议将POH截留在水包油壳聚糖纳米乳剂中，旨在通过鼻内给药来靶向大脑。开发了一种超高效液相色谱/串联质谱法（UPLC–MS / MS），并已用于定量大鼠血浆和脑中总代谢物紫苏酸（PA）。用乙腈进行液-液萃取，处理了含有代谢产物的大鼠样品。流动相是在水中的0.1％甲酸（溶剂A）和在甲醇中的0.1％甲酸（溶剂B），流速为0.3 mL min ^-1在梯度洗脱中。色谱运行10分钟，并在乙腈，血浆和脑中建立分析曲线。在多反应监测下以正离子模式检测到PA。该方法显示出高选择性，灵敏度和通量。162、178和121 ng mL ^-1的低定量限分别用于乙腈，脑和血浆时，表明该方法具有良好的可检测性。观察到的可重复性和精密度在文献中推荐的范围内。通过高回收率（106–118％）验证了该方法的准确性。经鼻腔给予大鼠游离或POH纳米乳剂后，已验证的方法已成功应用于代谢产物PA的药代动力学研究。结果表明，壳聚糖纳米乳液改善了POH的血浆和脑生物利用度，代表了免费POH治疗的有希望的替代方法。