Disposition of Bisantrene in Humans and Rabbits: Evidence for Intravascular Deposition of Drug as a Cause of Phlebitis 1

The investigational ant i tumor agent bisantrene (9 ,10-anthracenedicarboxaldehyde b is [ (4 ,5-d ihydro-1Himidazol -2-y l )hydrazone] d ihydrochlor ide) causes f requent local compl icat ions of phlebitis and thromboses in patients receiving the drug by peripheral venous infusion. Bisantrene pharmacokinet ics was studied in five patients. Plasma elimination was biphasic with t~/2 o~ of 65 min and t l /2 [~ of 1142 min; the mean apparent volumes of distr ibution of the central compar tment and peripheral compartments were 185 and 1 662 l i ters /sq m, suggest ing extensive uptake, binding, or deposit ion of drug. Total body clearance was 735 m l / m i n / s q m, and 11.3% of drug was excreted in urine. One hr after bisantrene (260 m g / s q m) at 1 mg/m l in 5% dextrose was infused into the marginal ear vein of a rabbit, the vein was congested with blood and contained 2.1 mg precipi tated bisantrene. After 24 hr, the vein was clotted and contained 1.1 8 mg precipi tated drug. Precipitat ion of bisantrene appears to be related to the low solubil i ty of the drug at physiological pH. Maximum solubil i ty of bisantrene in human and rabbit serum was 1 2.7 f fg/ml. Intravascular precipitation of bisantrene may be responsible for phlebit is and thromboses in humans receiving the drug by i.v. infusion.