This proposal addresses the effects of deranged hepatic function upon metabolism, excretion, toxicity and antitumor response of antineoplastic compounds. Doxorubicin (DOX) is proposed as a model of an hepatically handled antineoplastic agent. Improved understanding of the effects of specific hepatic lesions upon antineoplastic drug metabolism and pharmacodynamics in a well controlled model will allow the design of targeted, specific trials in humans, not only for older compounds such as Dox, but for newer, hepatically metabolized promising investigational compounds. It is hypothesized that 1) hepatic centrilobular, periportal, midzonal and metastatic tumor produce distinct perturbations in drug metabolism and drug induced toxicity due to variation in local cellular con-centrations of drug specific metabolizing isoenzymes. 2) Compounds which inhibit or induce hepatic drug metabolizing enzymes will pertrub the metabolism of antineoplastic agents in a manner different from those that occur when liver cells are killed or the liver parenchyma is replaced by tumor. Since the studies proposed here are not possible in humans, a rabbit model is used.
Specific aims i nclude the: 1) use of bromobenzene or carbon tetrachloride to produce hepatic centrilobular lesions, furosemide to produce midzonal lesions, allyl formate to produce periportal lesions, and an hepatically implanted VX-2 carcinoma to produce hepatic lesions; 2) evaluation of Dox pharmacokinetics and toxicity in rabbits with the above hepatic lesions; 3) evaluation of the effects of hepatic microsomal induction and inhibition upon the in vivo metabolism and toxicity of Dox in rabbits; 4) correlation of in vivo with in vitro Dox metabolism in microsomal preparations from livers of rabbits with deranged hepatic function; 5) correlation of in vivo and in vitro Dox metabolism and toxicity with physiologic pharmacokinetics. Paired Dox pharmacokinetic studies will be performed in animals without, then in the same animals with sublethal, toxin induced, acute hepatic lesions, and in animals pretreated with pharmacologic microsomal inducer (ethanol), inhibitor (diazepam) and a cytochrome P-450 reductase inhibitor (CuDIPS). Dox and doxorubicinol rates of metabolism in healthy and perturbed liver microsomes will be measured. For physiologic pharmacokinetics, animals with normal and perturbed hepatic function will be sacrificed at timed intervals after Dox administration. Organs, plasma and urine will be assayed for Dox and metabolites, Data from all studies will be fit to physiologic and classical pharmacologic models using nonlinear regression analysis.
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