Effects of lipophilicity and protein binding on the hepatocellular uptake and hepatic disposition of two anthracyclines, doxorubicin and iododoxorubicin.
The anthracyclines, in particular doxorubicin (DOX), have been used for the intra-arterial locoregional therapy of liver tumours for over two decades. However, the results obtained with this form of therapy have been disappointing. It is widely recognised that DOX has a slow and limited tissue uptake, and we hypothesised that lipophilic analogues could be more suitable for locoregional administration. Using rat hepatocyte suspensions and the isolated rat liver, we examined the effects of lipophilicity, as determined from the octanol: buffer partition coefficient (Koct:buf), and protein binding of several anthracyclines on hepatocellular uptake. In particular, we compared DOX with 4'-iodo-4'-deoxy-doxorubicin (IDX), which differs only in the substitution of the daunosamine hydroxyl by an iodine molecule. Using a direct spectrofluorimetric method to evaluate cell uptake, we found that the influx rates correlated with the logarithm of Koct:buf and that IDX had the highest rate. However, the addition of bovine serum albumin (BSA) to the medium reduced the hepatocellular uptake of IDX more extensively than that of DOX such that the DOX uptake exceeded that of IDX with 4% BSA. Experiments in the isolated perfused rat liver confirmed these findings. We suggest that a trade-off of cellular uptake for reduced protein binding is desirable in the selection of drugs for intrahepatic administration. This may be accomplished by choosing anthracyclines with intermediate lipophilicity.
Rivory
L P
LP
Department of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Australia.
Avent
K M
KM
Pond
S M
SM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D010477:Perfusion; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility
D000903:Antibiotics, Antineoplastic; C053044:4'-deoxy-4'-iododoxorubicin; D004317:Doxorubicin