Xu, Ruichao
(2022)
ASSESSMENT OF HEPATIC METABOLIC FUNCTION OF THE DONOR AND THE RECIPIENT IN LIVING DONOR LIVER TRANSPLANTATION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Liver is the largest solid internal organ in the human body. It is involved in vital functions, such as uptake of chemicals, synthesis of proteins, metabolism of endogenous and exogenous compounds, biliary secretion, homeostasis, and so on. Liver transplantation remains the only treatment option for patients with end-stage liver disease. Liver transplantation is traditionally performed with cadaveric donors (deceased donor liver transplantation, DDLT), whereas living donor liver transplantation (LDLT) has been increasingly performed in the US and other countries recently. Contrasting DDLT, LDLT involves the transplantation of a partial liver graft from the donors to the recipients, rather than a whole liver. The partial liver will regenerate back to its normal size in 2-6 months after the transplantation in donors and recipients, but the functional recovery accompanying the change of size is not fully understood. In this current work, we evaluated the time course of hepatic metabolic functional recovery in both LDLT donors and recipients in a prospective study by applying a metabolic probe cocktail approach, and assessed important covariates that could impact the functional recovery in LDLT recipients by PBPK and popPK modeling. We observed that LDLT recipients had lower tacrolimus clearance comparing DDLT recipients immediately post-surgery, potentially due to the incomplete liver size. We also found that while graft size is a significant covariate, it alone cannot account for the metabolic functional difference between donors and recipients. In addition, age, sex, body weight and total bilirubin level were identified as significant covariates associated with tacrolimus clearance. We estimated the recovery half-life of tacrolimus clearance in recipients to be 16 days. Further evaluation of functional recovery of 6 phase I and phase II metabolic pathways in donors and recipients showed relatively quick recovery, but not every pathway was equally impacted by the liver surgery. In general, donors reached full functional recovery faster than recipients, albeit starting with a smaller liver following a right-lobe transplantation post-surgery. Interestingly, sulfotransferase(SULT) was the only pathway that showed higher activity in recipients, which could be due to more inflammatory status in recipients, and could potentially be mediated by the inductive effect of TNF-alpha on sulfation.
In conclusion, we documented the time course of metabolic capacity recovery in both LDLT donors and recipients for the first time, and identified several significant covariates that would impact tacrolimus clearance in the recipients population. In general, .liver metabolic function recovers quickly compared to liver volume. Future studies in evaluating other aspects of liver function, such as transporter functions and/or other important metabolic and secretory pathways, will be critical to provide important guidance on precise dose selection in LDLT population.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
21 December 2022 |
| Date Type: |
Publication |
| Defense Date: |
17 August 2022 |
| Approval Date: |
21 December 2022 |
| Submission Date: |
14 December 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
274 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Living donor liver transplantation, hepatic metabolic capacity, tacrolimus, metabolic probe cocktails |
| Date Deposited: |
21 Dec 2022 15:00 |
| Last Modified: |
21 Dec 2022 15:00 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/40178 |
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