Fatty acid binding protein is a major determinant of hepatic pharmacokinetics of palmitate and its metabolites.
Disposition kinetics of [(3)H]palmitate and its low-molecular-weight metabolites in perfused rat livers were studied using the multiple-indicator dilution technique, a selective assay for [(3)H]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 [(3)H]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 [(3)H]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 [(3)H]palmitate also increased with increasing L-FABP levels. It is concluded that the variability in hepatic pharmacokinetics of unchanged [(3)H]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.
Hung
Daniel Y
DY
Department of Medicine, Princess Alexandra Hospital, University of Queensland, Woolloongabba, Queensland 4102, Australia.
Burczynski
Frank J
FJ
Chang
Ping
P
Lewis
Andrew
A
Masci
Paul P
PP
Siebert
Gerhard A
GA
Anissimov
Yuri G
YG
Roberts
Michael S
MS
D000418:Albumins / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D015415:Biomarkers; D001711:Biotransformation; D002352:Carrier Proteins / Q000378:metabolism*; D002994:Clofibrate / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004058:Diffusion; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005978:Glutathione / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010168:Palmitates / Q000493:pharmacokinetics*; D010477:Perfusion; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000418:Albumins; D015415:Biomarkers; D002352:Carrier Proteins; C493320:Fabp1 protein, mouse; C493321:Fabp1 protein, rat; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D000960:Hypolipidemic Agents; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010168:Palmitates; D011506:Proteins; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione; D002994:Clofibrate