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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Evaluation of Tributyrin Lipid Emulsion with Affinity to Low-Density Lipoprotein: Pharmacokinetics in Adult Male Wistar Rats and Cellular Activity on Caco-2 and HepG2 Cell Lines

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore, Singapore (J.S., P.C.H.); Department of Pediatrics, The First Affiliated Hospital of China Medical University, Shenyang, China (L.H.); and Department of Pharmacology, Faculty of Medicine, National University of Singapore, Singapore, Singapore (N.Z.)

The tributyrin lipid emulsion was proved to be able to bind to low-density lipoprotein (LDL) in vitro. The aim of this study was to investigate the pharmacokinetics of the emulsion in vivo and the cellular activity in vitro. The pharmacokinetics of tributyrin and its metabolite, butyrate, was evaluated in male Wistar rats after administration with pure tributyrin or tributyrin emulsion. After oral administration, maximal plasma concentration (C_max), time to reach maximal plasma concentration (T_max), and elimination half-life (T_1/2) of butyrate were 87.6 µM and 25.3 and 63.0 min, respectively, for the pure tributyrin compared with 1344.5 µM and 8.5 and 19.8 min for the 10% (v/v) tributyrin emulsion. C_max and mean residence time of tributyrin were 2.74 µM and 87.9 min and 4.2 µM and 132.0 min for pure tributyrin and 10% emulsion, respectively. The bioavailabilities of the pure tributyrin versus tributyrin emulsion were 15.3 versus 65.7% and 34.9 versus 64.5% calculated from butyrate and tributyrin, respectively. After the rats were treated with 17-ethynylestradiol (an LDL receptor up-regulator), the distribution volumes calculated from both butyrate and tributyrin were significantly increased after oral administration or infusion of the 10% tributyrin emulsion. The increased distribution volume after coadministration with a LDL receptor up-regulator suggested the increased uptake of tributyrin/butyrate by tissues with increased expression of LDL receptors. The selective uptake of the emulsion by the cellular LDL receptors was further confirmed by testing the cellular viability in the presence of competing LDL. The viable cells can reach 92% of control at IC₅₀ in Caco-2 and 77% in HepG2 incubated with emulsion in the presence of LDL.

Address correspondence to: Dr. Paul C. Ho, Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543. E-mail: phahocl{at}nus.edu.sg

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