The hepatic pharmacokinetics of five selected cationic drugs (propranolol, labetalol, metoprolol, antipyrine, and atenolol) was studied in the liver from control rats and from those with high-fat emulsion-induced nonalcoholic steatohepatitis (NASH). Studies were undertaken using an in situ-perfused rat liver and multiple indicator dilution, and outflow data were analyzed with a physiologically based organ pharmacokinetic model. Hepatic extraction (E) was significantly lower in the NASH model, and lipophilicity was the main solute structural determinant of the observed differences in intrinsic elimination clearance (CLint) and permeability-surface area product (PS) with pKa defining the extent of sequestration in the liver [apparent distribution ratio (Kv)]. The main pathophysiological determinants were liver fibrosis, leading to a decreased PS, liver fat causing an increase in Kv, and an increase in both total liver cytochrome P450 (P450) concentration and P450 isoform expression for Cyp3a2 and Cyp2d2, causing an increase CLint in NASH rat livers compared with control livers. Changes in hepatic pharmacokinetics (PS, Kv, CLint, and E ratio) as a result of NASH were related to the physicochemical properties of drugs (lipophilicity or pKa) and hepatic histopathological changes (fibrosis index, steatosis index, and P450 concentration) by stepwise regression analysis. Thus, it appears that in NASH, counteracting mechanisms to facilitate hepatic removal are created in NASH-induced P450 expression, whereas NASH-induced fibrosis and steatohepatitis inhibit E by decreasing hepatocyte permeability through fibrosis and hepatic sequestration.
Footnotes
This work was supported by the National Health and Medical Research Council of Australia [Grant 569710].
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.036806.
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ABBREVIATIONS:
- NASH
- nonalcoholic steatohepatitis
- P450
- cytochrome P450
- CLint
- intrinsic elimination clearance
- E
- hepatic extraction
- FI
- fibrosis index
- HDL
- high-density lipoprotein
- IPRL
- in situ-perfused rat liver
- koff
- intracellular unbinding rate constant
- RT-PCR
- reverse transcription-polymerase chain reaction
- kon
- intracellular binding rate constant
- kout
- efflux rat constant
- Kv
- apparent distribution ratio
- KR
- equilibrium amount ratio charactering the fast binding process
- Ks
- equilibrium amount ratio characterizing the slow binding process
- LDL
- low-density lipoprotein
- logCLint
- logarithm of intrinsic elimination clearance
- logKv
- logarithm of apparent distribution ratio
- logPapp
- logarithm of octanol/water partition coefficient
- logPS
- logarithm of permeability-surface area product
- MID
- multiple indicator dilution
- MTT
- mean transit time
- PS
- permeability-surface area product
- SI
- steatosis index
- TG
- triglyceride
- vLDL
- very low density lipoprotein.
- Received October 20, 2010.
- Accepted January 18, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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