The effects of impaired liver function on the elimination of antineoplastic agents

OBJECTIVE: To critically review available data on the disposition of cancer chemotherapy in patients with hepatic dysfunction, and to derive at dose recommendation. DATA SOURCES: All published studies in English. STUDY SELECTION: Both human and animal studies. DATA SYNTHESIS: The available studies were sequentially qualitatively described and critically discussed. The liver is responsible for the metabolism and elimination of many anticancer agents. Their accumulation during hepatic insufficiency may expose the patient to increased risk of drug toxicity. A variety of clinical methods have been described to estimate the need to decrease doxorubicin dose according to degree of hepatic failure to avoid serious toxicity. In some studies prospective ascertainment of clinical indices such as hepatic enzymes and bilirubin was successful in preventing doxorubicininduced hepatotoxicity. Liver dysfunction has a major impact on cyclophosphamide pharmacokinetics. However, because such impairment leads to less production of the active aldophosphamide, fewer adverse effects were observed in hepatically impaired patients. Vinca alkaloids are extensively metabolized by the liver and excreted in the bile. Systemic exposure to these drugs is inversely correlated to the degree of hepatic failure measured by serum alkaline phosphatase. Although hepatic metabolism is a major route of elimination of fluorouracil, the kidney also plays an important role in its elimination. It has been suggested to reduce its dose in cirrhotic patients. Available pharmacokinetic data and their clinical implications are also discussed for azathioprine, mercaptopurine, etoposide, epirubicin, amsacrine, cytarabine, and other less-studied drugs. Recommendations for dose adjustments are presented and discussed.