Intranasal administration of perillyl alcohol–loaded nanoemulsion and pharmacokinetic study of its metabolite perillic acid in plasma and brain of rats using ultra‐performance liquid chromatography/tandem mass spectrometry

Abstract

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.

Enhancing Oral Bioavailability and Brain Biodistribution of Perillyl Alcohol Using Nanostructured Lipid Carriers

“…Considering the properties of POH, such as low water solubility and low polarity, which pose challenges for its determination by ESI in the UPLC/MS-MS method, a decision was made to quantify the perillyl acid (PA), a metabolite of POH. Furthermore, due to the rapid metabolism of POH to PA, the levels of PA in plasma and brain were quantified instead [ 24 , 50 ].…”

“…Consequently, these advancements have the potential to minimize undesirable side effects and address the limitations associated with conventional cancer treatments [ 22 , 23 ]. Our research group has successfully developed a nanoemulsion containing POH, which exhibited enhanced bioavailability and brain targeting when administered intranasally in rats [ 24 ]. However, we are now eager to explore an alternative nanoparticle system for the same purpose, with a specific focus on oral administration.…”

The Monoterpenoid Perillyl Alcohol: Anticancer Agent and Medium to Overcome Biological Barriers

“…For instance, Zhang et al reported on their detection of intact POH and perillic acid in plasma from a patient after oral delivery of POH using gas chromatographic-mass spectrometry (GC-MS) [114]. In studies with mice or rats, other groups applied ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) [115] or high-performance liquid chromatography (HPLC)-ultraviolet (UV)-based approaches [116] to quantitate POH (and perillic acid) in the plasma and lungs of animals after intranasal delivery of POH. In a very recent study that investigated the impact of intranasal POH in a mouse model of cerebral malaria, the authors succeeded in quantifying POH in brain tissue using GC-MS [117].…”

Bovine Serum Albumin Nanoparticles Enhanced the Intranasal Bioavailability of Silybin in Rats

“…This can be particularly advantageous for drugs with low oral bioavailability, as well as for patients who have difficulty swallowing or require rapid onset of action. As a result, this approach holds promise for improving therapeutic outcomes and enhancing patient compliance [ 26 , 27 , 28 ].…”