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Articles in PresS, published online ahead of print November 20, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00328.2002
Submitted on August 6, 2002
Accepted on November 7, 2002
1 Department of Medicine, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia
2 Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada
3 Institute of Pharmaceutical Sciences, University of Nottingham, Nottingham, United Kingdom
* To whom correspondence should be addressed. E-mail: dhung{at}medicine.pa.uq.edu.au.
The disposition kinetics of [3H]palmitate and its low molecular weight metabolites in perfused rat livers were studied using the multiple indicator dilution technique, a selective assay for [3H]palmitate and its low molecular weight metabolites, and several physiologically based pharmacokinetic models. The level of liver fatty acid binding protein (L-FABP), other intra-hepatic binding proteins (microsomal protein, albumin, and glutathione S-transferase) and the outflow profiles of [3H]palmitate and metabolites were measured in four experimental groups: (i) male; (ii) clofibrate-treated male; (iii) female; and (iv) pregnant female rats. A slow diffusion/bound model was found to better describe the hepatic disposition of unchanged [3H]palmitate than other pharmacokinetic models. The L-FABP levels followed the order: pregnant female > clofibrate-treated male > female > male. The levels of other intra-hepatic proteins did not differ significantly. The hepatic extraction ratio and mean transit time for unchanged palmitate, as well as the production of low molecular weight metabolites of palmitate and their retention in the liver, increased with increasing L-FABP levels. Palmitate metabolic clearance, permeability-surface area product, retention of palmitate by the liver, and cytoplasmic diffusion constant for unchanged [3H]palmitate also increased with increasing L-FABP levels. It is concluded that the variability in hepatic pharmacokinetics of unchanged [3H] palmitate and its low molecular weight metabolites in perfused rat livers is related to levels of L-FABP and not those of other intra-hepatic proteins.
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