MURINE TOXICOLOGY AND PHARMACOLOGY OF UAB-8, A CONFORMATIONALLY CONSTRAINED ANALOG OF RETINOIC ACID

(2E, 4E, ohexen-1'-ylidene]-3,7-dimethyl-2,4,6-octatrienoic acid (UAB- 8) has potent activity in preventing papillomas on the skin of mice si milar to that determined in a previous study for the homolog containin g 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. Mic e dosed with UAB-8, however, had a lower incidence of clinical signs o f toxicity (alopecia, scaly skin, and limping). At necropsy, bone frac tures, 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 comparabl e teratogenic effects. For mice dosed iv (10 mg/kg), there was a satur ated phase of elimination of RA from plasma (K-m = 0.61 mu g/ml and V- max = 2572 mu g/hr); no such phase was noted when UAB-8 was administer ed. UAB-8 had values for t(1/2 alpha) and t(1/2 beta) of 0.47 and 17.1 hr, respectively. Relative to RA, UAB-8 has a favorable toxicological profile and different pharmacokinetics. (C) 1996 Academic Press, Inc.