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Am J Physiol Gastrointest Liver Physiol 284: G423-G433, 2003. First published November 20, 2002; doi:10.1152/ajpgi.00328.2002
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Vol. 284, Issue 3, G423-G433, March 2003

Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites

Daniel Y. Hung1, Frank J. Burczynski2, Ping Chang1, Andrew Lewis3, Paul P. Masci1, Gerhard A. Siebert1, Yuri G. Anissimov1, and Michael S. Roberts1

1 Department of Medicine, Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland Qld 4102, Australia; 2 Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2; and 3 Institute of Pharmaceutical Sciences, University of Nottingham NG7 2RD, United Kingdom

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 intrahepatic binding proteins (microsomal protein, albumin, and glutathione S-transferase) and the outflow profiles of [3H]palmitate and metabolites were measured in four experimental groups of rats: 1) males; 2) clofibrate-treated males; 3) females; and 4) pregnant females. 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. Levels of other intrahepatic 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 intrahepatic proteins.

clofibrate; pregnancy; multiple indicator dilution; hepatic extraction ratio; cytoplasmic diffusion constant


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