Intestinal Lymphatic Transport of Halofantrine Occurs After Oral Administration of a Unit-Dose Lipid-Based Formulation to Fasted Dogs

AbstractPurpose. To examine whether the small quantities of lipid present in unit-dose microemulsion formulations comprising medium- (C8-10) or long-chain (C18) glyceride lipids can stimulate the intestinal lymphatic transport of halofantrine (Hf), a model lymphatically transported drug. Methods. Hf (50 mg) was administered to thoracic lymph duct- and cephalic vein-cannulated fasted greyhound dogs. Drug was formulated as a single soft gelatin capsule containing approximately 1 g of a microemulsion preconcentrate based on either medium- or long-chain glycerides. Thoracic lymph was collected, and systemic plasma samples taken over 10 h postdose. Results. The extent of lymphatic transport of Hf after administration of the long-chain lipid formulation was high (28.3% of dose), and significantly higher than that seen after administration of the medium-chain formulation (5.0% of dose). Plasma levels of Hf were not significantly different across the two formulations when assessed by AUC0-10h. Conclusions. This is the first study to demonstrate that the small amounts of lipid present within a single lipid-based dose form can support substantial intestinal lymphatic transport in the fasted state. Furthermore, microemulsions based on long-chain glycerides appear to be more effective with respect to lymphatic transport than the equivalent medium-chain formulation.