A Pilot, First-in-Human, Pharmacokinetic Study of 9cUAB30 in Healthy Volunteers

University of Wisconsin, Madison, WI 53792, USA.
Cancer Prevention Research (Impact Factor: 4.44). 12/2010; 3(12):1565-70. DOI: 10.1158/1940-6207.CAPR-10-0149
Source: PubMed


9cUAB30 is a synthetic analog of 9-cis-retinoic acid with chemopreventive activity in cell lines and in animal models. The purpose of this first-in-human evaluation of 9cUAB30 was to evaluate the single-dose pharmacokinetic profile and toxicity of the compound in healthy volunteers at 3 dose levels. This study enrolled 14 patients to receive a single dose of 5, 10, or 20 mg of 9cUAB30. Plasma and urine samples were collected to assess 9cUAB30 concentrations by a validated LC/MS MS method. 9cUAB30 was well tolerated, with 1 patient experiencing grade 2 toxicity and no grade 3 or 4 toxicities reported. T(max) occurred approximately 3 hours after dose administration with the plasma half-life ranging from 2.79 to 7.21 hours. AUC increased linearly across the examined dose range of 5 to 20 mg; C(max) was proportional to the log of the dose. The plasma clearance ranged from 25 to 39 L/h compared to the renal clearance which ranged from 0.018 to 0.103 L/h. 9cUAB30 has a favorable toxicity and pharmacokinetic profile, with oral availability and primarily hepatic metabolism. Further dose ranging studies with once a day dosing are underway.

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    • "We recently examined a series of RXR agonists employing gene expression arrays (Vedell et al. 2013). The agonists examined were Targretin (TRG) (the only clinically employed RXR agonist) (Farol and Hymes 2004; Rigas and Dragnev 2005; Gniadecki et al. 2007; Lansigan and Foss 2010) and two RXR-selective agonists, UAB30 and 4-Me-UAB30, (Muccio et al. 1998; Atigadda et al. 2003; Grubbs et al. 2006; Gorman et al. 2007; Kolesar et al. 2010). Recently the 3D structures of RXR homodimers were determined containing either TRG or UAB30 and a coactivator peptide (Boerma et al. 2014). "
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    ABSTRACT: The ability of the retinoid X receptors (RXRs) specific agonists (targretin [TRG] and UAB30) to alter rat liver gene and protein expression was determined using Affymetrix Exon arrays and high-performance liquid chromatography – tandem mass spectrometry (LC-MS/MS). TRG profoundly increases triglycerides levels while UAB30 does not. The expression patterns of transcripts or proteins from rat liver treated with TRG or UAB-30 were different from controls and each other. There were six times more gene transcripts identified than proteins. Differentially expressed RNAs or proteins were mapped into known gene ontology (GO) categories and GeneGo Metacore (KEGG) pathway maps. The GO categories which were highly overrepresented with differentially expressed RNAs (P < 10−16) were also overrepresented at the protein level. This high concordance of GO Terms was achieved despite the fact that typically ≤1/3 of the elements identified by gene expression were identified by proteomics. Within these GO categories, the magnitude of alterations induced by RXR agonists at the transcript and protein levels were correlated. When GO categories with moderate overrepresentation (10−5 < P < 10−9) were examined, there was greater discordance between the transcript and protein data. Examination of KEGG pathway maps with highly significant changes at both the protein and the RNA levels showed that the individual proteins/genes altered were often the same and changes were of similar magnitude; while KEGG pathways showed limited statistical significance and exhibited minimal overlap. Finally, metabolomics analysis of liver and serum identified altered expression of metabolites related to fatty acid oxidation and bile acid metabolism that were consistent with transcript/protein changes. We observed significant concordance between genomics and proteomics implying either can identify pathways modulated and can indirectly predict resulting physiologic effects.
    Full-text · Article · Dec 2014
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    • "and with varying ability to inhibit mammary cancer formation (Muccio et al., 1998; Atigadda et al., 2003;.Grubbs et al., 2006). One of these analogs (UAB30) did not increase serum triglycerides in rodents (Grubbs et al., 2006) and humans (Kolesar et al., 2010) but was nevertheless effective in preventing mammary cancers in rats. "
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    ABSTRACT: This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1-3), their nuclear and cytoplasmic functions, post-transcriptional processing, and recently reported ligands. Points of interest are the different changes in the ligand-binding pocket induced by variously shaped agonists, the communication of the ligand-bound pocket with the coactivator binding surface and the heterodimerization interface, and recently identified ligands that are natural products, those that function as environmental toxins or drugs that had been originally designed to interact with other targets, as well as those that were deliberately designed as RXR-selective transcriptional agonists, synergists, or antagonists. Of these synthetic ligands, the general trend in design appears to be away from fully aromatic rigid structures to those containing partial elements of the flexible tetraene side chain of 9-cis-retinoic acid. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
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