EFFECT OF ALLYL ALCOHOL-INDUCED SUBLETHAL HEPATIC DAMAGE UPON DOXORUBICIN METABOLISM AND TOXICITY IN THE RABBIT

  • 15 June 1987
    • journal article
    • research article
    • Vol. 47  (12) , 3259-3265
Abstract
A model of hepatic dysfunction in vivo has been developed in rabbits to determine effects of sublethal hypatocellular necrosis upon doxorubicin pharmacology. Eight New Zealand white rabbits were given 3 mg/kg doxorubciin 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 hepatoxicity 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 to doxorubicin-induced acute toxicity may be doxorubicinol.