The impact of ΔG on the oral bioavailability of low bioavailable therapeutic agents

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Journal of Pharmacology and Experimental Therapeutics


Low oral bioavailability continues to drive research toward 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 for hydrophilic markers and hydrophobic drugs across the small intestine and the blood brain barrier. ΔG, 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 ΔG on the oral bioavailability of low bioavailable therapeutic agents. 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 (PIs), or with ΔG (720 μg/kg)/PI. Serial blood samples were collected, and plasma was analyzed for radioactivity. After ID administration with ΔG/PI, Cmax significantly (p < 0.05) increased over a range of 197 to 5700%, whereas area under the plasma concentration time curve displayed significant increases extending over a range of 123.8 to 4990.3% for the investigated drugs. ΔG significantly increased the in vivo oral absorption of some low bioavailable drugs in the presence of PI. This study suggests that ΔG-mediated tight junction modulation, combined with metabolic protection, may be used to enhance the low oral bioavailability of certain drugs when administered concurrently.

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