Targeting of drug to the hepatocytes by fatty acids. Influence of the carrier (albumin or galactosylated albumin) on the fate of the fatty acids and their analogs.
OBJECTIVE
The aim of this study was to evaluate the potential of fatty acids as shuttles to deliver xenobiotic inside the hepatocytes as well as to study the mechanism of incorporation into isolated hepatocytes when bound to native albumin or galactosylated albumin. Theoretically, they can enter into the hepatocytes after recognition of the Fatty Acid Binding Protein (FABPPM), or remain bound to galactosylated proteins and enter into these cells by a process known as receptor mediated endocytosis after selective recognition of the asialoglycoprotein receptor (ASGPR).


METHODS
We synthesized a 3H-benzoyl adduct of lauric acid (BLA) (benzoyl adduct chosen to mimic any low molecular weight drug or contrast agent), and compared the behavior of BLA with oleic acid for their binding properties to carrier-proteins and the uptake mechanism by isolated hepatocytes.


RESULTS
No significant difference was found in the binding properties of BLA for albumin and galactosylated albumin. The incorporation into the hepatocytes was found essentially depending on the FABPPM transport system whenever BLA was bound to albumin or to galactosylated albumin in the incubation medium: indeed, the transport was inhibited by phloretin (inhibitor of sodium dependent transport), increased when the free part of BLA was higher, and BLA was recovered in the cytosolic fraction of the hepatocytes.


CONCLUSIONS
This study showed the convenience in using fatty acids as drug carriers possessing tropism for the hepatocytes.
Charbon
V
V
Department of Pharmaceutical Sciences, Catholic University of Louvain, Brussels, Belgium.
Latour
I
I
Lambert
D M
DM
Buc-Calderon
P
P
Neuvens
L
L
De Keyser
J L
JL
Gallez
B
B
D000418:Albumins / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003287:Contrast Media; D004337:Drug Carriers; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism*; D005690:Galactose / Q000378:metabolism*; D066298:In Vitro Techniques; D007850:Lauric Acids / Q000493:pharmacokinetics*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015394:Molecular Structure; D008970:Molecular Weight; D018996:Myelin P2 Protein / Q000378:metabolism; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D019301:Oleic Acid; D009829:Oleic Acids / Q000493:pharmacokinetics; D010693:Phloretin / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats
D000418:Albumins; D002352:Carrier Proteins; D003287:Contrast Media; D004337:Drug Carriers; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D007850:Lauric Acids; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009829:Oleic Acids; C030358:lauric acid; D019301:Oleic Acid; D010693:Phloretin; D005690:Galactose