Pharmacokinetics of chronically administered all-trans-retinoyl-beta-glucuronide in mice

After the subcutaneous injection of retinoyl beta -glucuronide (RAG), both RAG; and retinoic acid (RA), formed by the hydrolysis of RAG in vivo, achie ved peak plasma concentrations within 1-2 h. Thereafter, RA was rapidly cle ared from the plasma whereas RAG was eliminated much more slowly. No signif icant changes were noted in the peak (2 h) plasma levels of RAG for treatme nt periods up to 56 days (one injection of RAG/day), in the clearance rate of RAG from plasma, or in plasma retinol concentrations. Similarly, no cons istent decrease in plasma levels of the RA hydrolysis product was observed. Mice undergoing these long-term chronic treatments with RAG did not show a ny clinical manifestations of retinoid toxicity. Taken together, our findin gs that chronic dosing with RAG produces sustained levels of both the paren t compound and the RA hydrolysis product, combined with the apparent low to xicity of RAG, suggest that RAG could be a safe and useful alternative to s ome retinoids which are presently being utilized in the clinic. (C) 2000 El sevier Science B.V. All rights reserved.