Pharmacokinetics of a hepatic stellate cell-targeted doxorubicin construct in bile duct-ligated rats.
OBJECTIVE
Inhibition of hepatic stellate cell (HSC) proliferation is a relevant strategy to inhibit liver fibrosis. Coupling of antiproliferative drugs to the HSC-selective drug carrier mannose-6-phosphate-modified human serum albumin (M6PHSA) may lead to cell-selective inhibition of HSC proliferation. We coupled the antiproliferative drug doxorubicin (DOX) to this drug carrier and investigated the pharmacokinetics of this construct in a rat model of liver fibrosis, as well as in cultured HSC.


RESULTS
M6PHSA-DOX was cleared from the plasma in a biphasic manner. Upon i.v. injection of 4 microg kg(-1) (tracer), 2 and 20 mg kg(-1), the clearance in the distribution phase of drug disposition (CL(d)) significantly decreased from 9.7+/-0.7 to 4.7+/-2.3 and 1.0+/-0.1 ml kg(-1)min(-1), respectively. This indicates that saturation of clearance mechanisms occurs in this phase of drug disposition, likely reflecting saturable receptor-mediated uptake in the target cells. Gamma-camera studies revealed that the majority of the conjugate accumulated in the liver within 5 min, and immunohistochemical double-staining of liver sections demonstrated co-localization of the construct with HSC-markers. Simulation of the release of DOX from the carrier, after cellular uptake by HSC, showed that a gradual release of the drug takes place over a 9h period. Studies in cultured HSC illustrated that after 24h incubation with the conjugate, DOX was associated with the cell nucleus.


CONCLUSIONS
The rapid distribution of M6PHSA-DOX from the blood to HSC, in combination with the expected gradual release of DOX within these cells, make this construct a promising tool for achieving sustained and selective inhibition of HSC proliferation.
Greupink
Rick
R
Department of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, Groningen University Institute for Drug Exploration (GUIDE), Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Reker-Smit
Catharina
C
Proost
Johannes H
JH
van Loenen Weemaes
Anne-miek
AM
de Hooge
Marjolijn
M
Poelstra
Klaas
K
Beljaars
Leonie
L
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics; D001652:Bile Ducts / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000378:metabolism / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000378:metabolism; D016503:Drug Delivery Systems; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008026:Ligation; D008099:Liver / Q000166:cytology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D004337:Drug Carriers; D004317:Doxorubicin