All-trans-retinoyl-b-D-glucuronide (RAG) is an endogenous active metabolite of all-trans-retinoic acid (ATRA). In the present study, the pharmacokinetics of RAG was examined after the administration of a single intravenous does (5, 10, or 15 mmol/kg) and of multiple daily intravenous doses (5 mmol/kg) to rats for 8 days. The plasma concentrations of RAG and ATRA were measured by a reverse-phase HPLC method. A rapid distribution phase of approximately 1 h was observed in all of the rats after single or multiple doses. Thereafter, RAG was eliminated through a ®rst-order process, in accord with a typical two-compartment ®rst order pharmacokinetic pro®le. After single intravenous doses, the AUC of RAG increased proportionally with the dose and the clearance remained unchanged within the tested doses. There was no statistical signi®cant difference in distribution rate constants from central compartment to peripheral compartment (K 12 ) and from peripheral compartment to central compartment (K 21 ) between different doses. However, as the dose increased from 5 mmol/kg to 10 mmol/kg, the volume of distribution at the steady state (V ss ) and the volume of peripheral compartment (V p ) decreased signi®cantly ( p 0.05) from 1.290 AE 0.269, 0.928 AE 0.232. L/kg to 0.961 AE 0.149, 0.647 AE 0.107 L/kg, respectively. V ss and V p at a dose of 15 mmol/kg (0.924 AE 0.187, 0.698 AE 0.165 L/kg) were not signi®cantly different from that at 10 mmol/kg. Thus, RAG might saturate the tissue-binding sites at higher doses. ATRA was detected as a metabolite of RAG at low levels (usually 0.05 mM) only in the ®rst 2 h after intravenous administration. RAG clearly was not extensively hydrolyzed to ATRA in our study. After multiple daily intravenous administration of RAG, the clearance (Cl) and the elimination rate constant (K 10 ) remained unchanged (p b 0.05), indicating that long-term daily administration of RAG did not induce its accelerated metabolism. However, K 12 , V p , and V ss declined signi®cantly ( p 0.05) from 1.67 AE 0.54 h À1 , 0.928 AE 0.232 L/kg, and 1.290 AE 0.269 L/kg to 0.96 AE 0.48 h À1 , 0.494 AE 0.147 L/kg, and 0.818 AE 0.187 L/kg, respectively. Therefore, long-term daily dosing of RAG seemed to decrease its distribution pro®le. Although the AUC of RAG did not change signi®cantly after multiple dosing, the AUC of ATRA after RAG dosing signi®cantly declined ( p 0.05) from 0.032 AE 0.019 mMÁh to 0.010 AE 0.006 mMÁh. The decline in the AUC of ATRA might re¯ect an increase in its uptake by tissue and/or in its metabolism. Because enhanced clearance is not associated with RAG after multiple