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Centrilobular hepatocyte contribution to doxorubicin (DOX) metabolism and myelotoxicity was probed with bromobenzene (BRB), a known centrilobular 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 of DOX. Pharmacokinetics of DOX after BRB pretreatment was mildly changed from control. Significantly increased plasma concentrations of doxorubicinol and its aglycone product, 7-deoxydoxorubicinol aglycone, were detected. Treatment with BRB alone was not lethal; however, in three of seven rabbits, the combination of DOX and BRB was. The mortality appeared to be related to myelosuppression. We conclude that toxin-induced hepato-cellular necrosis causes increased DOX-induced myelotoxicity. Following BRB pretreatment, the relatively small pharmacokinetic changes of parent compound concentrations as compared with greater changes in plasma pharmacokinetics of its alcohol metabolites suggest systemic changes in drug metabolism and distribution in the setting of hepatic disease may be the cause of increased toxicity. |
