Liver fibrosis impairs hepatic pharmacokinetics of liver transplant drugs in the rat model.
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 CCl(4)-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 CCl(4)-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.
Zou
Yu-Hong
YH
Therapeutics Research Centre, School of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.
Liu
Xin
X
Khlentzos
Alexander M
AM
Asadian
Peyman
P
Li
Peng
P
Thorling
Camilla A
CA
Robertson
Thomas A
TA
Fletcher
Linda M
LM
Crawford
Darrell H G
DH
Roberts
Michael S
MS
D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000187:drug effects / Q000503:physiopathology; D002251:Carbon Tetrachloride / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects; D005665:Furosemide / Q000378:metabolism / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D016031:Liver Transplantation; D008297:Male; D008790:Metoprolol / Q000378:metabolism / Q000493:pharmacokinetics; D008954:Models, Biological; D009853:Omeprazole / Q000378:metabolism / Q000493:pharmacokinetics; D009929:Organ Size / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D011433:Propranolol / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013148:Spironolactone / Q000378:metabolism / Q000493:pharmacokinetics; D019172:Transplantation Conditioning; D014867:Water / Q000378:metabolism
D004364:Pharmaceutical Preparations; D014867:Water; D013148:Spironolactone; D005665:Furosemide; D011433:Propranolol; D002251:Carbon Tetrachloride; D008790:Metoprolol; D009853:Omeprazole