title: Single-dose safety and pharmacokinetic evaluation of fluorocoxib A: pilot study of novel cyclooxygenase-2-targeted optical imaging agent in a canine model.
abstract: We evaluated preclinical single-dose safety, pharmacokinetic properties, and specific uptake of the new optical imaging agent fluorocoxib A in dogs. Fluorocoxib A, N-[(5-carboxy-X-rhodaminyl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide, selectively binds and inhibits the cyclooxygenase-2 (COX-2) enzyme, which is overexpressed in many cancers. Safety pilot studies were performed in research dogs following intravenous (i.v.) administration of 0.1 and 1  mg/kg fluorocoxib A. Blood and urine samples collected three days after administration of each dose of fluorocoxib A revealed no evidence of toxicity, and no clinically relevant adverse events were noted on physical examination of exposed dogs over that time period. Pharmacokinetic parameters were assessed in additional research dogs from plasma collected at several time points after i.v. administration of fluorocoxib A using high-performance liquid chromatography analysis. The pharmacokinetic studies using 1  mg/kg showed a peak of fluorocoxib A (92±28  ng/ml) in plasma collected at 0.5 h. Tumor specific uptake of fluorocoxib A was demonstrated using a dog diagnosed with colorectal cancer expressing COX-2. Our data support the safe single-dose administration and in vivo efficacy of fluorocoxib A, suggesting a high potential for successful translation to clinical use as an imaging agent for improved tumor detection in humans.
authors.affiliation: The University of Tennessee, College of Veterinary Medicine, Department of Small Animal Clinical Sciences, Knoxville, Tennessee 37996, USA. mcekanov@utk.edu
authors.forename: Maria
authors.initials: M
authors.lastname: Cekanova
authors.forename: Md Jashim
authors.initials: MJ
authors.lastname: Uddin
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Legendre
authors.forename: Gina
authors.initials: G
authors.lastname: Galyon
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Bartges
authors.forename: Amanda
authors.initials: A
authors.lastname: Callens
authors.forename: Tomas
authors.initials: T
authors.lastname: Martin-Jimenez
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
mesh_terms: D000818:Animals; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000662:veterinary; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D004283:Dog Diseases / Q000188:drug therapy / Q000378:metabolism; D004285:Dogs; D005260:Female; D005456:Fluorescent Dyes / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D007275:Injections, Intravenous; D008297:Male; D023421:Models, Animal; D061848:Optical Imaging / Q000379:methods*; D055620:Optical Phenomena; D010865:Pilot Projects; D012235:Rhodamines / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; D012235:Rhodamines; C579286:fluorocoxib A; D051546:Cyclooxygenase 2