Toxicologic and carcinogenic effects of the type IV phosphodiesterase inhibitor RP 73401 on the nasal olfactory tissue in rats

RP 73401, a type TV phosphodiesterase inhibitor, caused toxic effects in th e nasal olfactory region of Sprague-Dawley rats when administered by either oral or inhalation exposure. A single oral administration of RP 73401 (at a dose of greater than or equal to 50 mg/kg) or 5-day inhalation exposure ( 1 hr/day) at a dose of approximately 1.0 mg/kg per day caused degeneration and sloughing of the olfactory surface epithelium. Degeneration and loss of Bowman's glands were noted in the underlying lamina propria and submucosa. Electron microscopy of these lesions demonstrated that sustentacular cells and the epithelial cells lining Bowman's glands were the primary target ce lls in the olfactory mucosa. The earliest urtrastructural changes detected in these cells were dilatation and vesiculation of the endoplasmic reticulu m, suggesting that metabolic activation is important for the toxic effects. In repeated-dose studies, 13 wk of oral dosing at 2.0 or 6.0 mg/kg per day resulted in subtle disorganization of the olfactory epithelium, whereas ba sal cell hyperplasia in the olfactory epithelium was identified in a 6-mont h inhalation study at a dose of 1.0 mg/kg per day. A 2-yr inhalation carcin ogenicity study resulted in tumors of the nasal olfactory region in rats tr eated at 0.5 and 1.0 mg/kg per day. Most tumors were classified as olfactor y neuroblastomas, and immunohistochemistry on selected tumors was consisten t with their being of neuroectodermal origin. Of the species studied (rat, mouse, and dog), the olfactory toxicity of RP 73401 was confined to the rat , and the toxicity was likely related to metabolic activation by olfactory epithelial cells rather than the phosphodiesterase activity of the compound .