Hepatocellular necrosis, fibrosis and microsomal activity determine the hepatic pharmacokinetics of basic drugs in right-heart-failure-induced liver damage

Li, Peng, Robertson, Thomas A., Zhang, Qian, Fletcher, Linda M., Crawford, Darrell H. G., Weiss, Michael and Roberts, Michael S. (2012) Hepatocellular necrosis, fibrosis and microsomal activity determine the hepatic pharmacokinetics of basic drugs in right-heart-failure-induced liver damage. Pharmaceutical Research, 29 6: 1658-1669.


Author Li, Peng
Robertson, Thomas A.
Zhang, Qian
Fletcher, Linda M.
Crawford, Darrell H. G.
Weiss, Michael
Roberts, Michael S.
Title Hepatocellular necrosis, fibrosis and microsomal activity determine the hepatic pharmacokinetics of basic drugs in right-heart-failure-induced liver damage
Journal name Pharmaceutical Research   Check publisher's open access policy
ISSN 0724-8741
1573-904X
Publication date 2012-06
Sub-type Article (original research)
DOI 10.1007/s11095-012-0690-z
Volume 29
Issue 6
Start page 1658
End page 1669
Total pages 12
Place of publication New York, United States
Publisher Springer New York
Collection year 2013
Language eng
Formatted abstract Purpose: To explore how liver damage arising from cardio-hepatic syndromes in RHF affect the hepatic pharmacokinetics of basic drugs.
Methods: The hepatic pharmacokinetics of five selected basic drugs with different physicochemical properties were studied in IPRL from control rats and rats with RHF. Hepatic pharmacokinetic modelling was performed with a two-phase physiologically-based organ pharmacokinetic model with the vascular space and dispersion evaluated with the MID technique. The liver damage arising from RHF was assessed by changes in liver biochemistry and histopathology. The expression of various CYP isoforms was evaluated by real-time RT-PCR analysis.
Results:
Four of the five basic drugs had a significantly lower E in RHF rat livers compared to the control rat livers. Hepatic pharmacokinetic analysis showed that both the CL int and PS were significantly decreased in the RHF rat livers. Stepwise regression analysis showed that the alterations in the pharmacokinetic parameters (E, CL int and PS) can be correlated to the observed histopathological changes (NI, CYP concentration and FI) as well as to the lipophilicity of the basic drugs (log P app).
Conclusions: Serious hepatocellular necrosis and fibrosis induced by RHF affects both hepatic microsomal activity and hepatocyte wall permeability, leading to significant impairment in the hepatic pharmacokinetics of basic drugs.
Keyword Fibrosis index
Hepatic pharmacokinetics
Hepatocellular necrosis
In situ perfused rat liver
Right heart failure
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
 
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