Abstract
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(dXL/dt)ss and drug (dDL/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 (KX) and drug (KD) from the LLPP into the lymph from the washout kinetics. The mass of lipid (XLP) and drug (DLP) 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.
Footnotes
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doi:10.1124/jpet.105.094094.
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ABBREVIATIONS: TG, triglyceride; FA, fatty acid; LLPP, lymph lipid precursor pool; LPC, l-α-lysophosphatidylcholine; BS, bile salt; OA, oleic acid; Hf, halofantrine; PL, phospholipid; (dXL/dt)ss, steady-state rate of total FA transport into lymph; KX, first order rate constant describing FA transport from the lymph lipid precursor pool into the lymph; KXO, pseudo-zero order rate constant for lipid transport from the lymph lipid precursor pool into the lymph; XLP, mass of lipid in the lymph lipid precursor pool; (dDL/dt)ss, steady-state rate of drug transport into lymph; KDO, pseudo-zero order rate constant for drug transport from the lymph lipid precursor pool into the lymph; KD, first order rate constant describing drug transport from the lymph lipid precursor pool into the lymph; DLP, mass of drug in the lymph lipid precursor pool; ANOVA, analysis of variance.
- Received August 11, 2005.
- Accepted October 24, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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