An examination of the effect of intestinal first pass extraction on intestinal lymphatic transport of saquinavir in the rat.

PURPOSE: To assess the impact of intestinally based efflux/elimination processes on the extent of intestinal lymphatic transport of saquinavir. To compare the relative effects of co-administration of P-gp/CYP modulators on intestinal lymphatic transport versus systemic bioavailability of saquinavir.

METHODS: A cremophor mixed micelle formulation of saquinavir alone, or co-administered with P-gp/CYP modulators, verapamil, ketoconazole or cyclosporine, was dosed intraduodenally in the mesenteric lymph duct cannulated anaesthetized rat model.

RESULTS: Co-administration of P-gp/CYP modulators resulted in significant increases in the extent of intestinal lymphatic transport of saquinavir. A comparison of the relative enhancement of lymphatic transport and plasma bioavailability compared to control (i.e. saquinavir alone) reveals a greater effect of verapamil and ketoconazole on the amount of drug transported by the lymphatic route, an observation consistent with a preferential targeting of saquinavir via the intestinal lymphatics. In contrast co-administration of cyclosporine increased both the extent of lymphatic transport (5.5-fold), and systemic bioavailability (4.1-fold).

CONCLUSIONS: Intestinal P-gp/CYP efflux/elimination restricts saquinavir transport via the intestinal lymphatics in the rat. Targeted increases in intestinal lymphatic levels of saquinavir may be achieved by selective inhibition of intestinal P-gp and/or CYP.