EFFECT OF SUBLETHAL LIVER-INJURY ON DOXORUBICIN METABOLISM

Centrilobular hepatocyte contribution to doxorubicin (DOX) metabolism and myelotoxicity was probed with bromobenzene (BRB), a known centrilo bular hepatotoxin. New Zealand White rabbits were given DOX, 3 mg/kg i ,v, After 4 weeks, the rabbits were pretreated i.p. with 2.6 ml/kg 40% solution of BRB in corn oil followed 72 h later with a 3-mg/kg dose o f DOX, Pharmacokinetics of DOX after BRB pretreatment was mildly chang ed from control. Significantly increased plasma concentrations of doxo rubicinol and its aglycone product, 7-deoxydoxorubicinol aglycone, wer e detected. Treatment with BRB alone was not lethal; however, in three of seven rabbits, the combination of DOX and BRB was. The mortality a ppeared to be related to myelosuppression. We conclude that toxin-indu ced hepatocellular necrosis causes increased DOX-induced myelotoxicity . Following BRB pretreatment, the relatively small pharmacokinetic cha nges of parent compound concentrations as compared with greater change s in plasma pharmacokinetics of its alcohol metabolites suggest system ic changes in drug metabolism and distribution in the setting of hepat ic disease may be the cause of increased toxicity.