Received for publication June 24, 2004.
Revised September 15, 2004.
Accepted for publication September 15, 2004.

THE EFFECT OF G ON THE ORAL BIOAVAILABILITY OF LOW BIOAVAILABLE THERAPEUTIC AGENTS

Abstract

Objective: Low oral bioavailability continues to drive research towards identifying novel approaches to enhance drug delivery. Over the past few years, emphasis on the use of absorption enhancers has been overwhelming despite their major adverse effects. Zonula Occludens Toxin (Zot) was recently established as a safe and effective absorption enhancer, reversibly opening the tight junctions (tj) for hydrophilic markers and hydrophobic drugs across the small intestine and the blood brain barrier. G, the biologically active fragment of Zot, was isolated and shown to increase the in vitro transport and in vivo absorption of paracellular markers. The objective of this study was to examine the effect of G on the oral bioavailability of low bioavailable therapeutic agents. Methods: Jugular vein cannulated Sprague Dawley rats were randomly assigned to receive the following treatments intraduodenally (ID): [³H]Cyclosporin A, [³H]ritonavir, [³H]saquinavir or [³H]acyclovir at (120 µci/kg) alone, with protease inhibitors (PI), or with G (720 µg/kg)/PI. Serial blood samples were collected and plasma was analyzed for radioactivity. Results: After ID administration with G/PI, C_max significantly (p <0.05) increased over a range of 153.8 % to 5700 %, whereas AUC0- t displayed significant increases extending over a range of 123.8 % to 4990.3 % for the investigated drugs. Conclusions: G significantly increased the in vivo oral absorption of low bioavailable drugs in the presence of PI. This study suggests that G-mediated tj modulation, combined with metabolic protection, may be used to enhance the low oral bioavailability of drugs when administered concurrently.

Key words: Delta G, Zot, absorption enhancer, bioavailability, oral absorption, tight junctions