Tight junction modulation and its relationship to drug delivery.
In order for therapeutic agents to exert their pharmacological effects, they have to cross the biological membranes into the systemic circulation and reach the site of action. Drugs cross the membranes by one of two pathways; paracellular or transcellular. Most drugs are transported transcellularly depending on their physiocochemical properties, however the paracellular route is usually the main route of absorption for hydrophilic drugs (proteins, peptides, etc.). The paracellular pathway is governed by the tight junctions (TJs). The modulation of the TJs by absorption enhancers for paracellular drug transport enhancement and hence drug delivery improvement has been hampered for so many years by lack of comprehensive understanding of the structure and function of the TJs. The TJs are a multiple unit structure composed of multiprotein complex that affiliates with the underlying apical actomyosin ring. TJ proteins identified include transmembrane proteins; occludin and claudin, and cytoplasmic plaque proteins; ZO-1, ZO-2, ZO-3, cingulin, and 7H6. Among the new absorption enhancers that evolved in the past few years is Zonula Occludens toxin, Zot. In vivo and in vitro studies have shown that Zot and its biologically active fragment DeltaG could be effectively used to increase the transport/absorption of paracellular markers and low bioavailable drugs across the intestinal epithelium. Above all, the transient opening of the TJs by Zot suggests that it could be used as a novel approach for the safe drug delivery of therapeutic agents.
Salama
Noha N
NN
Pharmacokinetics-Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, 100 Penn Street, Baltimore, Maryland 21201, USA.
Eddington
Natalie D
ND
Fasano
Alessio
A
D000818:Animals; D002772:Cholera Toxin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems; D004731:Endotoxins; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D019108:Tight Junctions / Q000378:metabolism*
D004731:Endotoxins; D004364:Pharmaceutical Preparations; C077728:zonula occludens toxin, Vibrio cholerae; D002772:Cholera Toxin