Murine Toxicology and Pharmacology of UAB-8, a Conformationally Constrained Analog of Retinoic Acid

• Published in: Toxicology and applied pharmacology 1996-08, Vol.139 (2), p.310-316
• Main Authors: Lin, Tsu-Han, Rogers, Tina S., Hill, Donald L., Simpson-Herren, Linda, Farnell, Daniel R., Kochhar, Davendra M., Alam, Muzaffar, Brouillette, Wayne J., Muccio, Donald D.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Body Weight - drug effects; Calcification, Physiologic - drug effects; Chemotherapy; Erythrocyte Count; Female; Hematocrit - adverse effects; Hemoglobins - drug effects; Keratolytic Agents - pharmacology; Keratolytic Agents - therapeutic use; Keratolytic Agents - toxicity; Limb Buds - drug effects; Lymph Nodes - drug effects; Lymph Nodes - pathology; Medical sciences; Mice; Papilloma - prevention & control; Pharmacology. Drug treatments; Skin - drug effects; Skin - pathology; Skin Neoplasms - prevention & control; Tretinoin - analogs & derivatives; Tretinoin - chemistry; Tretinoin - pharmacokinetics; Tretinoin - pharmacology; Tretinoin - therapeutic use; Tretinoin - toxicity
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1996.0170

(2E, 4E, 6E)-8-[3′-Ethyl-2′-(1-methylethyl)-2′-cyclohexen-1′-ylidene]-3,7-dimethyl-2,4,6-octatrienoic acid (UAB-8) has potent activity in preventing papillomas on the skin of mice similar to that determined in a previous study for the homolog containing one less carbon atom. To evaluate the toxicological profile for UAB-8, relative to all-trans-retinoic acid (RA), female mice were dosed by oral gavage for 29 days with amounts of 0.05, 0.1, or 0.2 mmol/kg/day. For the two compounds, the effects on body weights were similar. Mice dosed with UAB-8, however, had a lower incidence of clinical signs of toxicity (alopecia, scaly skin, and limping). At necropsy, bone fractures, skin abnormalities, and splenomegaly were observed in some mice dosed with RA but not in any dosed with UAB-8. Lymph node hyperplasia was noted in some mice dosed with either dose of RA but only in those dosed with the highest dose of UAB-8. All dose levels of RA produced microscopic lesions in the bones of mice; only the highest dose of UAB-8 had this effect. RA and UAB-8 had similar effects on chondrogenesis in cultures of cells from mouse limb buds, an indication of comparable teratogenic effects. For mice dosed iv (10 mg/kg), there was a saturated phase of elimination of RA from plasma (Km= 0.61 μg/ml andVmax= 2572 μg/hr); no such phase was noted when UAB-8 was administered. UAB-8 had values fort1/2αandt1/2βof 0.47 and 17.1 hr, respectively. Relative to RA, UAB-8 has a favorable toxicological profile and different pharmacokinetics.