Received for publication October 31, 2005.
Revised January 29, 2006.
Accepted for publication January 31, 2006.

An examination of the interplay between enterocyte-based metabolism and lymphatic drug transport in the rat

Abstract

The current study has examined whether drugs that are transported to the systemic circulation via the intestinal lymph (and therefore associate with lipoproteins within the enterocyte) are accessible to enterocyte-based metabolic processes. The impact of changes to the mass of lipid present within the enterocyte-based lymph lipid precursor pool (LLPP) on the extent of enterocyte-based drug metabolism has also been addressed. Low (5 mg oleic acid/h) or high (20 mg oleic acid/5.2 mg lyso-phosphatidylcholine (LPC)/h) lipid dose formulations containing halofantrine (which is lymphatically transported and metabolised) or DDT (which is lymphatically transported and relatively metabolically inert) and radiolabelled oleic acid were infused into the duodenum of lymph-duct cannulated rats. After 5 h, drug and radiolabelled oleic acid were removed from the infusions allowing calculation of the first order turnover rate constants describing drug and oleic acid transport from the LLPP into lymph from the washout profiles. In one group of animals bolus doses of ketoconazole were also administered to inhibit cytochrome P450 based metabolism. The rate constant describing halofantrine transport from the LLPP into the lymph was lower than that of oleic acid, whereas these differences were abolished in the presence of ketoconazole. DDT and oleic acid exhibited similar turnover rate constants. The data therefore suggest that enterocytebased metabolism removes halofantrine from the LLPP prior to transport into the lymph. Furthermore, enhancing the lymphatic transport of halofantrine by co-administration of larger quantities of lipid reduced the difference between the turnover rate constant for halofantrine and oleic acid and appeared to reduce the extent of enterocyte-based metabolism.

Key words: absorption, cytochrome P450, drug disposition, drug transport, intestinal bioavailability, intestinal transport