Hepatic regeneration is essential for the success of living donor liver transplantation (LDLT) in which the residual liver in donor and the segment that is transplanted into the recipient will grow in size to accommodate the requirements of the donor and recipient. We hypothesized that the clearance of drugs will be drastically reduced during the immediate post operative period in donor and recipient due to reduced liver mass and the decreased activity of the drug metabolizing enzymes in the liver. The objectives of this dissertation are to evaluate 1) the mRNA expression and in vitro and in vivo activity (pharmacokinetics of tacrolimus) of CYP3A; 2) the effect of hepatotropic drugs such as cyclosporine and tacrolimus on the activity of CYP3A; 3) the expression, and in vitro and in vivo activity (pharmacokinetics of mycophenolic acid) of various uridine diphosphate glucuronosyltransferases; and 4) the in vivo metabolism of acetaminophen in rats, during hepatic regeneration after partial hepatectomy.
Our results indicate that 1) the activity of most of the drug metabolizing enzymes was decreased but recovered completely at different rates; 2) the mRNA expression mirrored the changes in in vitro activity of these enzymes; 3) the clearance of tacrolimus and mycophenolic acid was decreased but recovered completely at different rates; 4) the magnitude of reduction in in vivo clearance of tacrolimus and mycophenolic acid was much less than what was predicted from the loss of liver mass and reduction in enzyme activity; 5) cyclosporine and tacrolimus did not have any significant effect on the recovery of activity of CYP3A, and 6) there was increased production of toxic metabolites of acetaminophen during regeneration.
The clinical implications of our study are as follows: 1) Drug dosing in LDLT patients should be carefully monitored. A less than proportionate decrease in dose relative to reduction in liver mass may be necessary for different drugs. 2) The drug elimination capacity of the liver recovers completely with time and normal hepatic function will be restored in subjects undergoing hepatic resection. 3) Recovery of hepatic function will proceed normally in presence of hepatotropic substrates such as cyclosporine A and tacrolimus.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04142005-000100 |
| Date | 18 May 2005 |
| Creators | Tian, Hui |
| Contributors | Stephen C. Strom, Michael A. Zemaitis, Wen Xie, Samuel M. Poloyac, Raman Venkataramanan |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04142005-000100/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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