Conversion of liposomal 5-fluoro-2'-deoxyuridine and its dipalmitoyl derivative to bile acid conjugates of alpha-fluoro-beta-alanine and their excretion into rat bile.
We studied the hepatic processing and biliary excretion of metabolites of the radiolabeled cytostatic agent 5-fluoro,-2'-deoxy[6-3H]uridine (FUdR) and its lipophilic derivative FUdR-dipalmitate incorporated in liposomes. After intracardial injection in rats, free FUdR was cleared from the circulation within minutes. When FUdR or FUdR-dipalmitate was encapsulated in multilamellar vesicles (MLVs) composed of distearoylphosphatidylcholine/dipalmitoylphosphatidylglycerol (DSPC/DPPG/CHOL, 10:1), as expected, the clearance of 3H label was substantially delayed; incorporation of 50 mol% cholesterol in the liposomal bilayer caused a 2-fold further reduction in elimination rate. Incorporation of FUdR-dipalmitate in small unilamellar vesicles (SUV) of similar composition produced a several-fold further decrease in elimination rate: more than 40% of the injected dose was still circulating after 6 h. The plasma concentration of free FUdR after administration of liposomal FUdR-dipalmitate was below the detection limit (5 x 10(-8) M) at any time. Although only about 9% of the administered radioactivity was excreted into the bile within 48 h after injection of [3H]FUdR, a rapid initial excretion rate was observed (4% of the injected dose in the first 2 h). The bile-associated radioactivity was identified mainly as the catabolite alpha-fluoro-beta-alanine (FBAL), conjugated with the three major bile acid species present in rat bile, i.e., muricholic acid, cholic acid and chenodeoxycholic acid in a ratio of 1:3:1. Liposome incorporation of FUdR or FUdR-dipalmitate did not affect the nature of the excretory products but caused a significant decrease in the initial rate at which label appeared in the bile (< 2% in 6 h).
van Borssum Waalkes
M
M
Laboratory of Physiological Chemistry, Groningen Institute for Drug Studies (GIDS), Groningen University, Netherlands.
Kuipers
F
F
Havinga
R
R
Scherphof
G L
GL
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D005467:Floxuridine / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008081:Liposomes / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014316:Tritium; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D001647:Bile Acids and Salts; D008081:Liposomes; D005467:Floxuridine; D014316:Tritium; D015091:beta-Alanine; C032348:alpha-fluoro-beta-alanine