Novel Measurements of Impaired Hepatobiliary and Intestinal Transport
AdvisorPolli, James E.
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Other TitlesUsing Multi-Fluorinated Bile Acids and In Vivo Magnetic Resonance Imaging to Measure Bile Acid Transport
AbstractTransporters are membrane-bound proteins that play critical roles in the pharmacokinetics of endogenous substances and drugs, including their enterohepatic recirculation. The overall objective of this dissertation was to devise and apply novel measurements to assess impaired hepatobiliary and intestinal transport. The first objective was to assess transport of novel bile acid analogues within the enterohepatic circulation. Multi-fluorinated bile acids (MFBA) were assessed for their potential utility as visual probes of transport within live mice using 19F magnetic resonance imaging (MRI). Results indicate that MFBA have the potential to be used as a novel diagnostic test for bile acid diarrhea. However, due to obstacles in commercialization of MFBA using 19F MRI, we developed and assessed the use of novel nitroxide-bile acid conjugates (NBAC) as a potential alternative approach using conventional MRI. However, these compounds did not interact with intestinal or hepatic bile acid transporters. The second objective was to evaluate metformin-mediated transport concerns. First, a comprehensive literature review of metformin was assembled in a biowaiver monograph to evaluate the risks of allowing a Biopharmaceutics Classification System (BCS)-based biowaiver. Second, the in vivo metformin-mediated repression of the bile salt export pump (BSEP) was assessed. We conducted a clinical study to assess the effect of oral metformin on the pharmacokinetics of BSEP probe substrates. Results indicate that metformin increased pravastatin plasma exposure due to repression of BSEP-mediated elimination of the drug, and reduced BSEP-mediated reabsorption of conjugated primary bile acids in plasma, which are otherwise highly recycled via enterohepatic recirculation. The third objective was to evaluate potential excipient risks in allowing BCS-based biowaivers. A comprehensive assessment was conducted regarding the current regulatory framework in drug formulation and an evaluation of excipients that have been classified as absorption-modifying excipients (AME). Polysorbate 80 is recognized as an AME based on in vitro and preclinical data. Thus, in a clinical study in 12 healthy adult volunteers, we assessed the effect of oral polysorbate 80 on various drugs. Results indicate that polysorbate 80 had no impact on valacyclovir, chenodeoxycholic acid, or enalaprilat absorption.
DescriptionUniversity of Maryland, Baltimore. Pharmaceutical Sciences. Ph.D. 2022
Keywordbile acid diarrhea
Bile Acids and Salts