The effect of ΔG on the transport and oral absorption of macromolecules

Delta G (ΔG) is the biologically active fragment of Zonula Occludens Toxin (Zot), an absorption enhancer, that reversibly opens the tight junctions of epithelial and endothelial cells in the small intestine and brain. This study evaluates the possible use of ΔG in enhancing the oral bioavailability of macromolecules using large paracellular markers as model agents. The transport of [14C]Inulin and [14C]PEG4000 was evaluated across Caco-2 cells with ΔG (0, 100, 180 μg/ml). The apparent permeability coefficients (Papp) were calculated. The in vitro toxicity of ΔG (180 μg/ml) was assessed. Sprague Dawley rats were dosed intraduodenally (ID) with the following treatments: [14C]Inulin or [14C]PEG4000 (30 μci/kg) w/o ΔG (720 μg/kg)/protease inhibitors (PI). Blood was collected and plasma was analyzed for radioactivity. ΔG (180 μg/ml) increased [14C]Inulin and [14C]PEG4000 Papp by 82.6 and 24.4%, respectively, without any toxicity. After ID administration with ΔG/PI, Cmax and AUC were significantly (p < 0.05) increased for both Inulin and PEG4000. However, Inulin displayed greater enhancement ratios in vitro and in vivo. This study suggests that ΔG may be used to enhance the oral bioavailability of macromolecules (e.g., proteins) after coadministration through modulation of paracellular transport. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1310–1319, 2004