A comparison of intestinal lymphatic transport and systemic bioavailability of saquinavir from three lipid-based formulations in the anaesthetised rat model

Saquinavir is a lipophilic, poorly water-soluble HIV protease inhibitor that undergoes extensive first-pass metabolism and exhibits poor oral bioavailability. Redirection of the absorption pathway of anti-HIV compounds from the portal blood to the HIV-rich intestinal lymphatics may enhance therapeutic efficacy and reduce the extent of the first-pass effect. This study investigates the potential of targeted intestinal lymphatic transport of saquinavir via a lipid formulation approach. Three formulations containing oleic acid were examined: cremophor-oleic acid mixed micelles, D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS)-oleic acid mixed micelles and an oleic acid microemulsion. The mesenteric lymph duct cannulated anaesthetised rat model was employed. Plasma and lymph samples were analysed by HPLC. Lymph triglyceride was measured using an enzymatic colorimetric technique. The extent of lymphatic transport from the lipid vehicles was 0.025-0.05% of the dose administered. The microemulsion produced higher and more prolonged mesenteric lymph concentrations than the micellar formulations. A strong correlation existed between the concentration of saquinavir in intestinal lymph and lymph triglyceride levels. The systemic bioavailability was estimated to be 8.5% and 4.8% for the cremophor mixed micelle and the microemulsion, respectively. The cremophor mixed micelles produced higher bioavailability than TPGS mixed micelles, implying that the nature of the surfactant can influence the distribution of drug between lymph and plasma.