Momper, Jeremiah
(2011)
Characterization of Renal Anionic Drug Transport Capacity in Kidney Transplant Recipients with Persistent BK Viremia: Pharmacokinetic and Pharmacodynamic Studies of Cidofovir.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Kidney transplantation is the treatment of choice for end-stage renal disease (ESRD), and drug therapy plays a significant role in the management of transplant recipients. A variety of commonly used drugs are actively secreted by transporters in the kidney, yet the functional expression and activity of these proteins in transplant patients has not been investigated. The first objective of this research was to characterize anionic tubular secretion capacity in kidney transplant recipients by evaluating the pharmacokinetics of cidofovir, a prototypical organic anion transporter substrate frequently used to treat BK virus infections in this patient population. A sensitive and specific analytical technique was developed to measure cidofovir concentrations in human plasma. Pharmacokinetic analysis of cidofovir in adult kidney transplant recipients suggested reduced OAT1-mediated secretion in these patients. The mechanistic basis of this observation was evaluated in a syngeneic rat model of kidney transplantation, which established that the transplant process itself leads to a sustained reduction in the expression of anionic transport proteins localized to the basolateral membrane of the renal proximal tubule. Additionally, apical anionic transporters were differentially regulated in this model.
The next objective was to evaluate the pharmacodynamics of cidofovir in kidney transplant patients. This study demonstrated that cidofovir transiently reduced the degree of BK viremia and viruria in vivo, though the effect was not sustained, and viral loads returned to baseline by the next sampling period. A retrospective analysis employed serum creatinine-based estimates of cidofovir clearance in a large cohort of kidney transplant recipients to approximate aggregate cidofovir exposure, and correlated drug exposure with virologic response. Higher systemic exposure was significantly associated with a larger reduction in the degree of BK viremia. However, only 11% of the variance in the decline in the BK viral load could be explained by variation in cumulative cidofovir exposure, indicating that other factors, likely immune-mediated, play a major role in viral clearance. Collectively, this work broadens our understanding of drug disposition in kidney transplant recipients and provides fundamental knowledge that may improve the treatment of BK virus infections.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
5 December 2011 |
| Date Type: |
Publication |
| Defense Date: |
29 September 2011 |
| Approval Date: |
5 December 2011 |
| Submission Date: |
21 November 2011 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
242 |
| 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: |
Pharmacokinetics; Pharmacodynamics; Cidofovir; BK Virus; Transplantation; Drug Transporters |
| Date Deposited: |
05 Dec 2011 20:26 |
| Last Modified: |
19 Dec 2016 14:38 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10657 |
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