EFFECTS OF LIPOPHILICITY AND PROTEIN-BINDING ON THE HEPATOCELLULAR UPTAKE AND HEPATIC DISPOSITION OF 2 ANTHRACYCLINES, DOXORUBICIN AND IODODOXORUBICIN

The anthracyclines, in particular doxorubicin (DOX), have been used fo r the intra-arterial locoregional therapy of liver tumours for over tw o decades. However, the results obtained with this form of therapy hav e been disappointing. It is widely recognised that DOX has a slow and limited tissue uptake, and we hypothesised that lipophilic analogues c ould be more suitable for locoregional administration. Using rat hepat ocyte suspensions and the isolated rat liver, we examined the effects of lipophilicity, as determined from the octanol: buffer partition coe fficient (K-oct: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 th e daunosamine hydroxyl by an iodine molecule. Using a direct spectrofl uorimetric method to evaluate cell uptake, we found that the influx ra tes correlated with the logarithm of K-oct:buf and that IDX had the hi ghest 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 findi ngs. We suggest that a trade-off of cellular uptake for reduced protei n binding is desirable in the selection of drugs for intrahepatic admi nistration. This may be accomplished by choosing anthracyclines with i ntermediate lipophilicity.