title: The effect of delta G on the transport and oral absorption of macromolecules.
abstract: Delta G (DeltaG) 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 DeltaG in enhancing the oral bioavailability of macromolecules using large paracellular markers as model agents. The transport of [(14)C]Inulin and [(14)C]PEG4000 was evaluated across Caco-2 cells with DeltaG (0, 100, 180 microg/ml). The apparent permeability coefficients (P(app)) were calculated. The in vitro toxicity of DeltaG (180 microg/ml) was assessed. Sprague Dawley rats were dosed intraduodenally (ID) with the following treatments: [(14)C]Inulin or [(14)C]PEG4000 (30 microci/kg) w/o DeltaG (720 microg/kg)/protease inhibitors (PI). Blood was collected and plasma was analyzed for radioactivity. DeltaG (180 microg/ml) increased [(14)C]Inulin and [(14)C]PEG4000 P(app) by 82.6 and 24.4%, respectively, without any toxicity. After ID administration with DeltaG/PI, C(max) 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 DeltaG may be used to enhance the oral bioavailability of macromolecules (e.g., proteins) after coadministration through modulation of paracellular transport.
authors.affiliation: Pharmacokinetics-Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 20 Penn Street, Baltimore, Maryland 21201, USA.
authors.forename: Noha N
authors.initials: NN
authors.lastname: Salama
authors.forename: Alessio
authors.initials: A
authors.lastname: Fasano
authors.forename: Manjusha
authors.initials: M
authors.lastname: Thakar
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Eddington
mesh_terms: D000042:Absorption / Q000187:drug effects / Q000502:physiology; D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002772:Cholera Toxin / Q000008:administration & dosage* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004731:Endotoxins; D006801:Humans; D046911:Macromolecular Substances / Q000008:administration & dosage* / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004731:Endotoxins; D046911:Macromolecular Substances; C077728:zonula occludens toxin, Vibrio cholerae; D002772:Cholera Toxin