GUO-DISSERTATION-2021.pdf (6.39 MB)

The Role of Gut Bacteria in Tacrolimus Disposition

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posted on 01.05.2021, 00:00 by Yukuang Guo
Tacrolimus is the mainstay immunosuppressant drug used after solid organ and hematopoietic stem cell transplantation. Tacrolimus exhibits a low and variable oral bioavailability, with an average of 25% of the oral dose reaching the systemic circulation. The major site of drug loss is in the gut, and the gut extraction ratio was reported as 85% and 74% in healthy and liver transplant patients, respectively. However, current known factors including CYP3A4/5 mediated drug metabolism and P-glycoprotein mediated drug efflux does not fully explain the drug loss. This suggest other contributing factors are yet to be well defined. In this project, we examined the possibility of tacrolimus being metabolized by bacteria that contribute to low oral drug exposure. Our results demonstrate bacterial metabolism of tacrolimus as an important elimination pathway in humans. In detail, human gut bacteria can convert tacrolimus to hydroxyl-tacrolimus, a much less active form, through ketone reduction and reduce tacrolimus oral exposure.

History

Advisor

Jeong, HyunyoungLee, Hyunwoo

Chair

Jeong, Hyunyoung

Department

Pharmaceutical Sciences

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Degree name

PhD, Doctor of Philosophy

Committee Member

Mankin, Alexander Orjala, Jimmy Lee, John Richard

Submitted date

May 2021

Thesis type

application/pdf

Language

en

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