Liver fibrosis impairs hepatic pharmacokinetics of liver transplant drugs in the rat model

Zou, Yu-Hong, Liu, Xin, Khlentzos, Alexander M., Asadian, Peyman, Li, Peng, Thorling, Camilla A., Robertson, Thomas A., Fletcher, Linda M., Crawford, Darrell H. G. and Roberts, Michael S. (2010) Liver fibrosis impairs hepatic pharmacokinetics of liver transplant drugs in the rat model. Drug Metabolism and Pharmacokinetics, 25 5: 442-449. doi:10.2133/dmpk.DMPK-10-RG-031

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Author Zou, Yu-Hong
Liu, Xin
Khlentzos, Alexander M.
Asadian, Peyman
Li, Peng
Thorling, Camilla A.
Robertson, Thomas A.
Fletcher, Linda M.
Crawford, Darrell H. G.
Roberts, Michael S.
Title Liver fibrosis impairs hepatic pharmacokinetics of liver transplant drugs in the rat model
Journal name Drug Metabolism and Pharmacokinetics   Check publisher's open access policy
ISSN 1347-4367
Publication date 2010
Sub-type Article (original research)
DOI 10.2133/dmpk.DMPK-10-RG-031
Open Access Status DOI
Volume 25
Issue 5
Start page 442
End page 449
Total pages 8
Place of publication Tokyo, Japan
Publisher Yakubutsu Dotai Gakkai (Japanese Society for the Study of Xenobiotics)
Collection year 2011
Language eng
Formatted abstract
This study aims to investigate hepatic pharmacokinetics of the four most common drugs (metoprolol, omeprazole, spironolactone, and furosemide) given to patients undergoing liver transplantation before surgery. The investigation was carried out in CCl4-induced fibrotic perfused rat livers and the results were compared to those in normal rat liver. Drug outflow fraction-time profiles were obtained after bolus injection into a single-pass-perfused normal or fibrotic rat liver. The pharmacokinetic parameters were estimated using previously developed barrier-limited and space-distributed models. The results showed a marked increase in the liver fibrosis index for CCl4-treated rats compared to controls (p<0.05). The extraction ratios (E) for all drugs were significantly lower (p<0.05) in fibrotic than in normal livers and the decrease in E was consistent with the decrease in intrinsic clearance and permeability-surface area product. In addition, other than for furosemide, the mean transit times for all drugs were significantly longer (p<0.01) in the fibrotic livers than in normal livers. Pharmacokinetic model and stepwise regression analyses suggest that these differences arise from a reduction in both the transport of drugs across the basolateral membrane and their metabolic clearance and were in a manner similar to those previously found for another group of drugs.
Keyword Hepatic pharmacokinetics
Liver fibrosis
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Medicine Publications
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Created: Tue, 16 Nov 2010, 11:11:16 EST by Dr Xin Liu on behalf of Medicine - Princess Alexandra Hospital