Evaluation of the Yucatan micropig for assessing the disposition and oral bioavailability of selected compounds
KeywordsHealth Sciences, Pharmacy.
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PublisherThe University of Arizona.
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AbstractDisposition and oral bioavailability studies involving non-rodent animal models traditionally rely upon the dog to predict human pharmacokinetics and oral bioavailability values during the preclinical phase of drug development. However, differences in oral absorption parameters suggest that the dog, in general, may fail to reasonably predict human values. The Yucatan micropig is proposed and examined as an alternative animal model for such studies. The presence and distribution of four major cytochrome P450 (CYP) enzymes (1A2, 2C19, 2D6, and 3A4) was characterized along the small intestine of the Yucatan micropig. Distribution patterns of these enzymes were similar to humans, especially for CYP3A4. CYP1A2, 2D6, and 3A4 content were greatest in the duodenum-upper jejunum region while CYP2C19 content was relatively consistent throughout the length of the small intestine. The quantity of CYP3A4 enzymes present was substantially greater than any of the other enzymes examined. To examine the validity of using swine to predict human values, an oral bioavailability study was conducted in Yucatan micropigs using antipyrine as a model compound. Rate and extent of absorption of antipyrine in humans were better predicted using the Yucatan micropigs as an animal model than any other species (rat, monkey, dog). After establishing the utility of the Yucatan micropig for absorption studies to predict human values, the disposition and bioavailability of components in two botanicals, turmeric and ginger, were examined. Curcumin, a major active component of turmeric, was found to have a very short terminal half-life due to, in part, a high blood clearance based on data obtained from several in vitro studies. Bioavailability of curcumin varied depending on the formulation administered. Large amounts of a glucuronide metabolite were detected after oral administration of curcumin indicating substantial pre-systemic metabolism. Unlike curcumin, 6-, 8-, and 10-gingerol, major putative components of ginger, were stable in blood. Terminal half-lives were only slightly longer than that for curcumin (10.5, 6.2, and 8.8 minutes, respectively). Formation of a glucuronide metabolite for each of the gingerols was observed after oral administration of capsules containing a crude ginger extract, but absent in the commercial product administered.
Degree ProgramGraduate College