A model of hepatic dysfunction in vivo has been developed in rabbits to determine the effects of sublethal hepatocellular necrosis upon doxorubicin pharmacology. Eight New Zealand white rabbits were given 3 mg/kg doxorubicin i.v. Plasma doxorubicin and metabolite pharmacokinetics were determined and toxicity assessed by nadir complete blood counts. Hepatic function was assessed by the pulmonary excretion rate of 14CO2 from [14C]aminopyrine. Hepatocellular necrosis was produced by i.v. injection of 1.35 mg/kg of a 2% allyl alcohol solution. Doxorubicin administration and pharmacokinetics were repeated.
Doxorubicin enhances the hepatotoxicity of allyl alcohol. Hepatocellular necrosis does not alter the plasma pharmacokinetics of doxorubicin but does increase the plasma exposure of doxorubicinol. Doxorubicin-induced myelosuppression is enhanced by allyl alcohol pretreatment. These data suggest that in circumstances of reduced hepatocellular volume or acute hepatocellular necrosis, a key plasma marker of doxorubicin-induced acute toxicity may be doxorubicinol.
↵1 This investigation was supported by the Veterans Administration, Clinical Research Center Grant RR 0095, American Cancer Society Institutional Grant IN25V, and NIH BRSG-RR-05425.
↵2 To whom requests for reprints should be addressed, at Department of Clinical Pharmacology and Therapeutics, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY, 14263.
- Received November 11, 1986.
- Revision received March 10, 1987.
- Accepted March 19, 1987.
- ©1987 American Association for Cancer Research.