title: Plasma pharmacokinetics and bioavailability of verticillin A following different routes of administration in mice using liquid chromatography tandem mass spectrometry.
abstract: Verticillin A is a natural product isolated from fungal cultures and has displayed potent antibiotic, antiviral, nematocidal, and anticancer properties in vitro. While in vivo studies have been limited due to sparse supply, the in vivo efficacy data that does exist demonstrates potent anti-tumor activity in murine cancer models. The current study aims to investigate the pharmacokinetics and bioavailability of verticillin A in mice to provide guidance for further efficacy assessment in mouse models. A sensitive and specific liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of verticillin A in mouse plasma. Sample preparation was accomplished through protein precipitation, and chromatographic separation was achieved on an Agilent Zorbax Extend C18 column with a security guard cartridge C8 using a binary gradient with mobile phase A (water/0.1% formic acid) and B (ACN/0.1% formic acid) at a flow rate of 400μl/min. Elution of verticillin A and internal standard, hesperetin, occurred at 4.87 and 2.06min, respectively. The total chromatographic run time was 8min, and the assay was linear in the concentration range of 1-1000nM. The within- and between day precisions and accuracy were in the range of 2.58-8.71 and 90-105%, respectively. The assay was applied to determine plasma drug concentration in a mouse pharmacokinetic study. It was found that intraperitoneal dosing of 3mg/kg resulted in high systemic exposure and achieved Cmaxof 110nM with plasma concentrations sustained above 10nM for the 24-h duration of the study. Intravenous and oral dosing achieved observed Cmaxof 73nM and 9nM, respectively. Oral dosing resulted in an approximate 9% bioavailability. Comparing with previously published in vitro studies that demonstrated verticillin A is active in the 20nM to 130nM range, the pharmacokinetic data demonstrate similar levels are achieved in mouse plasma via intravenous or intraperitoneal dosing routes.
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Pharmacy, The Ohio State University, Columbus, OH, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.
authors.forename: Shamala
authors.initials: S
authors.lastname: Kolli
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Mycosynthetix, Inc., 505 Meadowlands Dr., Suite 103, Hillsborough, NC 27278, United States.
authors.forename: Cedric J
authors.initials: CJ
authors.lastname: Pearce
authors.affiliation: Department of Chemistry & Biochemistry, University of North Carolina at Greensboro, P.O. Box 26170, Greensboro, NC 27402, United States.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States; College of Pharmacy, The Ohio State University, Columbus, OH, United States. Electronic address: phelps.32@osu.edu.
authors.forename: Mitch A
authors.initials: MA
authors.lastname: Phelps
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002853:Chromatography, Liquid / Q000379:methods; D005260:Female; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D007274:Injections, Intraperitoneal; D051379:Mice; D008813:Mice, Inbred ICR; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D007211:Indoles; C009654:verticillins
keywords: Epipolythiodioxopiperazine alkaloids; Liquid chromatography–mass spectrometry; Mouse; Pharmacokinetics; Plasma; Verticillin A