Hepatocellular necrosis, fibrosis and microsomal activity determine the hepatic pharmacokinetics of basic drugs in right-heart-failure-induced liver damage.
OBJECTIVE
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 (logP 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.
Therapeutics Research Centre, School of Pharmacy & Medical Sciences, Division of Health Sciences, University of South Australia Basil Hetzel Institute for Medical Research, Adelaide, SA, 5001, Australia. Peng.li@unisa.edu.au
Peng
P
Li
Thomas A
TA
Robertson
Qian
Q
Zhang
Linda M
LM
Fletcher
Darrell H G
DH
Crawford
Michael
M
Weiss
Michael S
MS
Roberts
D018674:Adrenergic Antagonists / Q000493:pharmacokinetics*; D000704:Analysis of Variance; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D000983:Antipyrine / Q000493:pharmacokinetics; D001262:Atenolol / Q000493:pharmacokinetics; D002463:Cell Membrane Permeability; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000150:complications*; D007741:Labetalol / Q000493:pharmacokinetics; D016014:Linear Models; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008790:Metoprolol / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D009336:Necrosis; D017711:Nonlinear Dynamics; D010477:Perfusion; D011433:Propranolol / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018674:Adrenergic Antagonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001262:Atenolol; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D008790:Metoprolol; D007741:Labetalol; D000983:Antipyrine