Effect of Bile on Absorption of Mepitiostane by the Lymphatic System in Rats

Abstract

The effects of bile and site of gastrointestinal absorption on the lymphatic absorption of the highly lipophilic drug, mepitiostane were examined using thoracic duct-cannulated rats. The lymphatic absorption from the small intestine was very small in the absence of bile compared with that when bile was present. The lymphatic absorption was greatest when drug was administered to the upper small intestine with bile, was smaller for the lower regions of the small intestine, and was negligible for the stomach and the large intestine. A correlation was observed between the extent of lymphatic absorption and the secretion of chylomicron and very low density lipoproteins after administration to various regions with or without bile. The portal absorption data of mepitiostane confirmed that site specificity occurs in the partition of drug between blood and lymph.

Bile Increases Intestinal Lymphatic Drug Transport in the Fasted Rat

“…Specifically, the study involved comparison of endogenous FA output in bile and endogenous FA and Hf transport in lymph following systematic addition of bile components (BS and LPC) to a low-dose exogenous FA containing formulation administered to fasted rats. Previous studies have examined lymphatic drug transport following bile diversion; however, this method complicates determination of the intrinsic ability of bile to enhance lymphatic drug transport because the solubilization of lipids within the intestinal lumen is compromised in the setting of bile diversion that subsequently reduces the efficiency of lipid absorption into the enterocyte (31,32). The current results indicate that endogenous FA in lymph that are recruited from bile more avidly support lymphatic transport of Hf than other sources of endogenous FA.…”

Lipid-based delivery systems and intestinal lymphatic drug transport: A mechanistic update

“…The ability of PL to enhance lymphatic transport has been elegantly demonstrated in studies using Mdr2 (−/−) mice where biliary phosphatidylcholine secretion is depleted (but normal biliary BS secretion remains). In these animals, postprandial formation of CM does not occur [8,14,166].…”

“…Lymphatic transport has been shown to be a contributor to the oral bioavailability of a number of highly lipophilic drugs and other xenobiotics following oral delivery, including: two lipophilic cannabinoids [184], halofantrine [11,12], moxidectin [13], mepitiostane [14,15], testosterone derivatives [16], MK-386 (a 5α-reductase inhibitor) [17], penclomedine [18], naftifine [19], probucol [20], cyclosporine [21], ontazolast [22], CI-976 [23], fat soluble vitamins and their derivatives, retinoids [24], lycopene, DDT and analogs [8,25], benzopyrene, PCBs (polychlorinated biphenyls) [26] and a number of lipophilic prodrugs [27][28][29]. In contrast, only very small quantities of more hydrophilic drugs such as salicylic acid, isoniazid and caffeine are recovered in lymph following oral delivery [8].…”

Intestinal lymphatic transport for drug delivery

“…Lymphatic drug transport has been reported to be a contributor in the oral bioavailability in various lipophilic drugs and xenobiotics after oral administration such as: dexabinol [272], moxidectin [123], halofantrine [94,122], mepitiostane [243,273], testosterone derivatives [91], penclomedine [178], naftifine [274], probucol [275], cyclosporine [276], ontazolast [277], retinoids and fat soluble vitamins [278], lycopene, DDT and analogs [247,279], benzopyrene, polychlorinated biphenyls (PCBs) [280], and various lipophilic drugs [232,248,258]. Also a very small number of hydrophilic drugs such as salicylic acid, isozianid and caffeine are recovered in small quantities in lymph after oral administration [279].…”