Pharmacokinetic study of all‐trans‐retinoyl‐β‐d‐glucuronide in Sprague–Dawley rats after single and multiple intravenous administration(s)

Abstract

All‐trans‐retinoyl‐β‐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 μmol/kg) and of multiple daily intravenous doses (5 μmol/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 first‐order process, in accord with a typical two‐compartment first order pharmacokinetic profile. 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 significant difference in distribution rate constants from central compartment to peripheral compartment (K12) and from peripheral compartment to central compartment (K21) between different doses. However, as the dose increased from 5 μmol/kg to 10 μmol/kg, the volume of distribution at the steady state (Vss) and the volume of peripheral compartment (Vp) decreased significantly (p < 0.05) from 1.290 ± 0.269, 0.928 ± 0.232. L/kg to 0.961 ± 0.149, 0.647 ± 0.107 L/kg, respectively. Vss and Vp at a dose of 15 μmol/kg (0.924 ± 0.187, 0.698 ± 0.165 L/kg) were not significantly different from that at 10 μmol/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 μM) only in the first 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 (K10) remained unchanged (p > 0.05), indicating that long‐term daily administration of RAG did not induce its accelerated metabolism. However, K12, Vp, and Vss declined significantly (p < 0.05) from 1.67 ± 0.54 h−1, 0.928 ± 0.232 L/kg, and 1.290 ± 0.269 L/kg to 0.96 ± 0.48 h−1, 0.494 ± 0.147 L/kg, and 0.818 ± 0.187 L/kg, respectively. Therefore, long‐term daily dosing of RAG seemed to decrease its distribution profile. Although the AUC of RAG did not change significantly after multiple dosing, the AUC of ATRA after RAG dosing significantly declined (p < 0.05) from 0.032 ± 0.019 μM·h to 0.010 ± 0.006 μM·h. The decline in the AUC of ATRA might reflect an increase in its uptake by tissue and/or in its metabolism. Because enhanced clearance is not associated with RAG after multiple administrations, RAG could be considered as an alternate to ATRA in appropriate clinical applications. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:2023–2031, 2001