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Intranasal Toxicity of BMS-181885, A Novel 5-HT1 Agonist

Department of Toxicology, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, New York, USA

Jim E. Proctor

Department of Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Syracuse, New York, USA

Mark A. Dominick

Department of Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Mt. Vernon, Indiana, USA

Amy E. Weiss

Department of Experimental Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Hopewell, New Jersey, USA

Oliver P. Flint

Department of Experimental Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Hopewell, New Jersey, USA

Nuggehally R. Srinivas

Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, USA

Stephen K. Durham

Department of Experimental Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Hopewell, New Jersey, USA

Beth E. Schilling

Department of Toxicology, Bristol-Myers Squibb Pharmaceutical Research Institute, Mt. Vernon, Indiana, USA

One-month intranasal toxicity studies were conducted with BMS-181885 at doses of 1.5, 9, or 15 mg/animal/day in rats and 4, 24, or 40 mg/animal/day in monkeys. A 1-month intermittent intranasal toxicity study was also conducted in monkeys at doses of 3, 6, and 12 mg/animal 3 days per week. BMS-181885 was generally well tolerated in rats but resulted in dose-dependent nasal mucosal injury, primarily characterized by subacute inflammation of the nasal mucosa, and degeneration, single-cell necrosis, and/or erosion of the olfactory epithelium and, to a lesser extent, the respiratory epithelium. In monkeys, daily BMS-181885 administration was well tolerated and produced similar dose-dependent nasal injury primarily characterized by subacute inflammation of the nasal mucosa with degeneration and erosion of the olfactory epithelium. In a separate experiment, intermittent administration also resulted in dose-dependent nasal injury. In cultured rat nasal mucosal cells, BMS-181885 was toxic to olfactory epithelial cells with a range of mean IC₅₀s between 44 and 291 µM. In contrast, BMS-181885 had no effect on respiratory epithelial cells up to its maximum solubility. Cytochrome P450 inhibition had no effect on the toxicity of BMS-181885 in olfactory epithelial cells but produced dose-dependent toxicity in respiratory epithelial cells, which was not present previously. The in vitro data suggest that parent drug, rather than a toxic metabolite, caused the drug-associated nasal mucosal injury.

Key Words: 5-HT Agonist • Intranasal Toxicity • In Vitro • In Vivo • Metabolism • Monkeys • Nasal Toxicity • P450 • Rats • Safety Assessment • Serotonin

International Journal of Toxicology, Vol. 18, No. 5, 285-296 (1999)
DOI: 10.1080/109158199225206


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