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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

The Lymph Lipid Precursor Pool Is a Key Determinant of Intestinal Lymphatic Drug Transport

Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Parkville, Victoria, Australia

The influence of the size and turnover kinetics of the enterocyte-based lymph lipid precursor pool (LLPP) on intestinal lymphatic drug transport has been examined. Mesenteric lymph duct-cannulated rats were infused intraduodenally with low (2-5 mg/h) or high (20 mg/h) lipid-dose formulations containing 100 µg/h halofantrine (Hf, a model drug) and 1 µCi/h ¹⁴C-oleic acid (OA) (as a marker for lipid transport) until steady-state rates of lipid(dX_L/dt)_ss and drug (dD_L/dt)_ss transport in lymph were obtained. After 5 h, the infusion was changed to formulations of the same composition but excluding ¹⁴C-OA and Hf, allowing calculation of the first order rate constants describing turnover of lipid (K_X) and drug (K_D) from the LLPP into the lymph from the washout kinetics. The mass of lipid (X_LP) and drug (D_LP) in the LLPP was also determined. Biliary-lipid output was determined in a separate group of rats that had been infused with the same formulations. The results indicate that after administration of high lipid doses, lymphatic drug transport is dependent on the mass of exogenous lipid available in the LLPP and the rate of lipid pool turnover into the lymph. In contrast, after administration of low lipid doses, biliary-derived endogenous lipids are most likely to be the primary drivers of drug incorporation into the LLPP and lymph. Therefore, the LLPP size and composition seem to be major determinants of lymphatic drug transport, and formulation components, which increase lipid pool size, may therefore enhance lymphatic drug transport.

Address correspondence to: Dr. Christopher J. H. Porter, Dept. of Pharmaceutics, Victorian College of Pharmacy, Monash University, 381 Royal Pde, Parkville, 3052 Victoria, Australia. E-mail: chris.porter{at}vcp.monash.edu.au

This article has been cited by other articles:

				N. L. Trevaskis, C. J.H. Porter, and W. N. Charman AN EXAMINATION OF THE INTERPLAY BETWEEN ENTEROCYTE-BASED METABOLISM AND LYMPHATIC DRUG TRANSPORT IN THE RAT Drug Metab. Dispos., May 1, 2006; 34(5): 729 - 733. [Abstract] [Full Text] [PDF]