Author ORCID Identifier
0009-0002-0460-797X
Defense Date
2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Pharmaceutical Sciences
First Advisor
Dr. Phillip M. Gerk
Abstract
Quercetin is a natural flavonoid with therapeutic potential, but its oral bioavailability is limited by poor aqueous solubility and extensive pre-systemic metabolism. Enzymatically modified isoquercitrin (EMIQ) is a soluble glucosylated precursor that releases quercetin upon sequential hydrolysis after oral administration and has emerged as a therapeutic lead for myotonic dystrophy type 1 (DM1). This dissertation tested the hypothesis that EMIQ shields quercetin from pre-systemic intestinal glucuronidation, improving oral bioavailability relative to direct quercetin aglycone ingestion.
A sensitive single-quadrupole LC-MS assay for quercetin was developed and partially validated in mouse and human plasma, requiring only 10 µL per sample (LLOQ 70 nM) to enable microsampling. In pooled human intestinal S9 fraction, hydrolytic release of quercetin from EMIQ exceeded its glucuronidation during initial times, and a well-stirred gut model predicted a fraction escaping intestinal metabolism of 88.3% for EMIQ-derived quercetin versus 20.6% for quercetin aglycone.
Rat and mouse skeletal muscle exhibited β-glucuronidase activity capable of deconjugating quercetin glucuronides, relevant to DM1 where skeletal muscle is an important target site. In FVB/n mice, oral EMIQ delivered 6.2-fold higher total quercetin exposure than equimolar quercetin. Apparent oral bioavailability was 38.2% for EMIQ versus 6.2% for quercetin, and true bioavailability (Ftrue) for free quercetin was 2.65%, the first such value reported for EMIQ.
Chronic 12-week dosing of EMIQ showed no systemic accumulation, while quercetin reached micromolar levels in skeletal muscle. Together with skeletal muscle β-glucuronidase activity, this explains how a low Ftrue could still support therapeutic activity, providing a framework for DM1 and beyond.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
6-11-2026