The antiviral protein human lactoferrin is distributed in the body to cytomegalovirus (CMV) infection-prone cells and tissues.
OBJECTIVE
Lactoferrin has anti-Cytomegalovirus (CMV) and -HIV properties in vitro. However, the pharmacokinetic behavior of the 80-kD protein has not been well defined. We, therefore, assessed the plasma decay and body distribution of lactoferrin after intravenous administration to freely moving rats. Furthermore, the systemic availability of lactoferrin after intraperitoneal dosing was determined.


RESULTS
After intravenous injection, human lactoferrin (hLF) was rapidly cleared from the plasma, but higher doses resulted in prolonged plasma levels. Immunohistochemical analysis revealed a pronounced distribution of hLF to endothelial cells in the liver whereas diffuse staining in hepatocytes indicated the presence of considerable amounts in this large cell population. This endothelial association, which also was found in other organ/tissues, including blood vessels. was confirmed by in vitro cell-binding studies. In addition, leukocytes in plasma that were infiltrated in various organs showed binding of hLF. A small fraction of hLF was transported into the lymphatic system. Western blot analysis revealed that hLF, present in the various organs. mainly consisted of an 80-kD protein. After intraperitoneal administration, small amounts of 80-kD hLF distributed to the general circulation. The bioavailability was 0.6% but increased to 3.6% after multiple administrations.


CONCLUSIONS
The affinity of hLF for endothelial cells and leukocytes, and its penetration into the lymphatic system, indicates that this protein reaches target cells and body compartments that are crucial for CMV and HIV replication. The ability to reach the blood compartment after intraperitoneal dosing offers opportunities for parenteral administration of the protein in future studies on its antiviral effects in vivo.
Beljaars
Leonie
L
Department of Pharmacokinetics and Drug Delivery, University Center for Pharmacy, Groningen University Institute for Drug Exploration, The Netherlands. L.Belijaars@farm.rug.nl
Bakker
Hester I
HI
van der Strate
Barry W A
BW
Smit
Catharina
C
Duijvestijn
Adrian M
AM
Meijer
Dirk K F
DK
Molema
Grietje
G
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D004727:Endothelium / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007781:Lactoferrin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008208:Lymphatic System / Q000378:metabolism; D008297:Male; D009928:Organ Specificity; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000998:Antiviral Agents; D007781:Lactoferrin