Hepatotoxicity of chemotherapeutic agents.

Abstract

I N PART because of its unique dual blood supply from the portal vein and the hepatic artery, the liver plays a central role in drug metabolism. Intravenous drugs reach the liver through the hepatic artery, and those given orally through the portal blood from the gut. The potential susceptibility of the liver to toxic drug reactions is thus not surprising. Paradoxically, many chemotherapeutic agents metabolized by the liver produce little or no hepatic damage. This apparent discrepancy has at least two explanations. First, most chemotherapeutic agents act preferentially on rapidly proliferating tissues such as the gastrointestinal tract, hair roots, and bone marrow, leading to the usual toxicities of mucositis, alopecia, and marrow suppression. The slowly dividing hepatocytes are less susceptible to such drugs. Second, the liver may metabolize a toxic agent to inactive or nontoxic metabolites, preventing liver damage. But, the reverse may also occur, i.e., transformation of an inactive compound into a hepatotoxic one. Determining if a chemotherapeutic drug is hepatotoxic is often difficult because of the multiplicity of potentially toxic events occurring in the cancer patient. Patients are usually exposed to a variety of medications, for both the tumor and the symptoms it causes, making it difficult to pinpoint any one as the cause of a particular side effect. The immunosuppressive effects of chemotherapy may predispose to complicating infections affecting the liver. Transfusion of blood products brings the risk of viral hepatitis. The liver is a common site of metastases that also alter its function.’ As a further complicating factor, the metabolism of many chemotherapeutic agents in humans is unclear. It is important, however, to identify those drugs known to be regularly hepatotoxic so they can be replaced, if possible, or so the dose can be modified to reduce toxicity. Drugs not toxic to the liver but metabolized there may also require dose reductions. The evidence for designating a drug as a hepatotoxin is often based upon case reports, retrospective analysis, and other, less satisfactory, means of identification. Although it is possible for any drug to produce an idiosyncratic