Evaluation of the Pharmacokinetics of All-Trans-Retinoic Acid (ATRA) in Wistar Rats After Intravenous Administration of ATRA Loaded into Tributyrin Submicron Emulsion and its Cellular Activity on Caco-2 and HepG2 Cell Lines

The pharmacokinetics of all-trans-retinoic acid (ATRA), an anti-cancer drug was highly variable due to its poor aqueous solubility. In this study, we investigated the pharmacokinetics of ATRA in male Wistar rats following intravenous administration of the ATRA loaded tributyrin emulsion. In vitro, the ATRA emulsion was proved binding to apolipoprotein(s). In vivo, the clearance of ATRA was significantly reduced by formulating into the tributyrin emulsion, leading to higher AUCs. Co-administration with 17α-ethynylestradiol, a compound known to upregulate the activity of low-density lipoprotein receptors in tissues, significantly increased the Ke, V, and CL of ATRA. The variation of plasma AUCs after administering the ATRA emulsion to the healthy rats was two times less than that after the ATRA solution. The IC50 in ATRA of the ATRA emulsion for the Caco-2 carcinoma cells was 3.8 µg/mL lower than 6 µg/mL of the ATRA solution. The IC50 of the emulsion for the HepG2 carcinoma cells was 2.8 µg/mL, while IC50 was not achieved with the ATRA solution over the test concentration range. The finding indicated that the tributyrin emulsion could be used as a carrier for ATRA and enhances the drug effect by reducing the clearance and increasing the in vitro activity. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:2844-2853, 2008