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The lymph lipid precursor pool is a key determinant of intestinal lymphatic drug transport.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2006 Feb; Vol. 316 (2), pp. 881-91. Date of Electronic Publication: 2005 Oct 25. - Publication Year :
- 2006
-
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 microg/h halofantrine (Hf, a model drug) and 1 microCi/h (14)C-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 (14)C-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.
- Subjects :
- Animals
Bile metabolism
Biological Transport
Drug Carriers administration & dosage
Intestinal Absorption
Lipids administration & dosage
Oleic Acid administration & dosage
Oleic Acid pharmacokinetics
Phenanthrenes administration & dosage
Phenanthrenes pharmacokinetics
Rats
Drug Carriers pharmacokinetics
Intestinal Mucosa metabolism
Lipids pharmacokinetics
Lymph metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3565
- Volume :
- 316
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 16249368
- Full Text :
- https://doi.org/10.1124/jpet.105.094094