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Simultaneous measurement of perillyl alcohol and its metabolite perillic acid in plasma and lung after inhalational administration in Wistar rats.

Abstract

Inhalational administration of drugs is a practical and non-invasive approach with the potential to reduce side effects and 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. We developed a detection method 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 standard MTT assay, and apoptosis markers were analyzed by Western blot. For the detection of POH and PA in lungs and plasma, we used albino Wistar rats 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.

Authors+Show Affiliations

Graduate Program in Medical Sciences, Fluminense Federal University, Niterói, Rio de Janeiro, 24033-900, Brazil.Department of Analytical Chemistry, Fluminense Federal University, Niterói, Rio de Janeiro, 24020-150, Brazil.Laboratory of Experimental Nutrition. Department of Nutrition and Dietetics, Fluminense Federal University, Niterói, Rio de Janeiro, 24033-900, Brazil.Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.Department of Neurosurgery, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, California, USA.Service of Neurosurgery, Department of General and Specialized Surgery, Antonio Pedro University Hospital, Fluminense Federal University, Niterói, Rio de Janeiro, 24033-900, Brazil.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31800149

Citation

Carneiro de Lima, Daniela, et al. "Simultaneous Measurement of Perillyl Alcohol and Its Metabolite Perillic Acid in Plasma and Lung After Inhalational Administration in Wistar Rats." Drug Testing and Analysis, 2019.
Carneiro de Lima D, Rodrigues SV, Boaventura GT, et al. Simultaneous measurement of perillyl alcohol and its metabolite perillic acid in plasma and lung after inhalational administration in Wistar rats. Drug Test Anal. 2019.
Carneiro de Lima, D., Rodrigues, S. V., Boaventura, G. T., Cho, H. Y., Chen, T. C., Schönthal, A. H., & Orlando da Fonseca, C. (2019). Simultaneous measurement of perillyl alcohol and its metabolite perillic acid in plasma and lung after inhalational administration in Wistar rats. Drug Testing and Analysis, doi:10.1002/dta.2722.
Carneiro de Lima D, et al. Simultaneous Measurement of Perillyl Alcohol and Its Metabolite Perillic Acid in Plasma and Lung After Inhalational Administration in Wistar Rats. Drug Test Anal. 2019 Dec 4; PubMed PMID: 31800149.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Simultaneous measurement of perillyl alcohol and its metabolite perillic acid in plasma and lung after inhalational administration in Wistar rats. AU - Carneiro de Lima,Daniela, AU - Rodrigues,Silvana Vianna, AU - Boaventura,Gilson Teles, AU - Cho,Hee-Yeon, AU - Chen,Thomas C, AU - Schönthal,Axel H, AU - Orlando da Fonseca,Clovis, Y1 - 2019/12/04/ PY - 2019/09/02/received PY - 2019/10/09/revised PY - 2019/10/21/accepted PY - 2019/12/5/entrez PY - 2019/12/5/pubmed PY - 2019/12/5/medline KW - HPLC KW - Perillyl alcohol KW - Ras oncoprotein KW - inhalation KW - perillic acid JF - Drug testing and analysis JO - Drug Test Anal N2 - Inhalational administration of drugs is a practical and non-invasive approach with the potential to reduce side effects and 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. We developed a detection method 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 standard MTT assay, and apoptosis markers were analyzed by Western blot. For the detection of POH and PA in lungs and plasma, we used albino Wistar rats 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. SN - 1942-7611 UR - https://www.unboundmedicine.com/medline/citation/31800149/Simultaneous_measurement_of_perillyl_alcohol_and_its_metabolite_perillic_acid_in_plasma_and_lung_after_inhalational_administration_in_Wistar_rats L2 - https://doi.org/10.1002/dta.2722 DB - PRIME DP - Unbound Medicine ER -