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

Abstract

After the subcutaneous injection of retinoyl beta-glucuronide (RAG), both RAG and retinoic acid (RA), formed by the hydrolysis of RAG in vivo, achieved peak plasma concentrations within 1-2 h. Thereafter, RA was rapidly cleared from the plasma whereas RAG was eliminated much more slowly. No significant changes were noted in the peak (2 h) plasma levels of RAG for treatment 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 consistent decrease in plasma levels of the RA hydrolysis product was observed. Mice undergoing these long-term chronic treatments with RAG did not show any clinical manifestations of retinoid toxicity. Taken together, our findings that chronic dosing with RAG produces sustained levels of both the parent compound and the RA hydrolysis product, combined with the apparent low toxicity of RAG, suggest that RAG could be a safe and useful alternative to some retinoids which are presently being utilized in the clinic.

In vitro and in vivo effects of easily administered, low-toxic retinoid and phenylacetate compounds on human neuroblastoma cells

“…In contrast, while maximal increases in the formation of neurites occurred at PA concentrations between 5 and 10 mM, 4-CPA was found to be about threefold more potent with maximal neurite-inducing activity occurring at about 3 mM. As previously reported (Sidell et al, 2000), RAG also induced neurite sprouting from LA-N-5 cells, with maximal effects seen at RAG concentrations in the 5 -10 mM range after extended periods (46 days). These morphologic changes are similar to those extensively reported after RA treatment of LA-N-5 cells (Sidell et al, 1983;Robson and Sidell, 1985), with the exception that maximal neurite outgrowth is seen with RA at somewhat lower concentrations (41 mM).…”

“…Previous studies have demonstrated the antiproliferative effects of RAG on LA-N-5 cells and indicated that this retinoid was 5 -10-fold less potent than RA on a concentration-dependent basis (Sidell et al, 2000). Figure 2 shows the dose-dependent effects of 4-CPA on the growth of LA-N-5 cells as assessed by SRB protein staining.…”

“…As such, we were interested in determining the effects on RARb expression of retinoids and 4-CPA at concentrations measured in the mice blood plasma during our treatment. For these experiments, real-time RT -PCR was used to determine relative mRNA levels of RARb in LA-N-5 cells treated for 2 days with RA, RAG, and 4-CPA at concentrations that were determined to be achieved in mouse blood plasma following chronic administration of RAG and 4-CPA as shown in our past (Sidell et al, 2000) and present work. To this end, our previous study showed that mean peak plasma levels of retinoids achieved during long-term daily administration of RAG by s.c. injection were approximately 0.5 mM RA (as a hydrolysis product of RAG) and 7.5 mM RAG.…”

“…RAG was administered by daily subcutaneous (s.c.) injections for the indicated time periods as previously described (Sidell et al, 2000). For treating with 4-CPA, the compound was given either by single intragastric administration (gavage) or admixed in their drinking water at the concentrations and time periods indicated in the long-term studies.…”

“…The reasons for this drug-free period every 2 weeks include the severe hypervitaminosis A side effects as well as the induction of increased RA metabolism that can occur in children undergoing continuous treatment with 13-cis RA (RuizMaldonado et al, 1998). Recently, we have demonstrated that longterm chronic dosing of mice with all-trans retinoyl b-glucuronide (RAG) is surprisingly lacking in toxicity and systemic adverse side effects that are usually associated with long-term retinoid therapy (Sidell et al, 2000). These studies showed that blood plasma concentrations of RAG in the micromolar ranges were maintained throughout the 2-month treatment protocol.…”