Although extensive guidelines have been published for the use of drugs in renal failure, few guidelines exist for the use of drugs when hepatic function is altered. In general, preexisting liver disease has little effect on elimination of most drugs unless Child’s class C cirrhosis is present.²⁸ Oral drugs with a high first-pass hepatic clearance are most likely to be affected. Agents metabolized by cytochrome P-450 oxidative pathways are more likely to have pharmacokinetic changes in liver disease than are those that are metabolized by glucuronidation.²⁸ However, the physician must often choose both drug and dose empirically. Table 20-5 outlines a dose modification scheme. Known hepatotoxic drugs must be avoided if hepatotoxicity develops but not in every setting of abnormal liver function.

The alkylating agents include the nitrogen mustards, ethyleneimines, alkylsulfonates, nitrosoureas, and triazenes. The nitrogen mustards that currently used in therapy are mechlorethamine, cyclophosphamide, bendamustine, melphalan, and chlorambucil. Mechlorethamine, given intravenously, rapidly undergoes chemical transformation and combines with either body water or reactive compounds. Hepatic metabolism is not considered important, and nitrogen mustard does not cause hepatic abnormalities, presumably because of its rapid degradation.²⁷

In an attempt to achieve greater selectivity for neoplastic tissues, the chemical structure of mechlorethamine was modified, resulting in cyclophosphamide. The liver cytochrome P-450 system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with its acyclic tautomeric form, aldophosphamide. In cells that are susceptible to cytolysis, nonenzymatic cleavage of aldophosphamide yields phosphoramide mustard and acrolein. These two compounds are highly cytotoxic and may represent active forms of the drug. In spite of its requirement for hepatic metabolism for activity, cyclophosphamide is an uncommon hepatic toxin, and only a few reports of elevated hepatic enzymes are attributed to the drug.^{28,29,30,31,32,33} Diffuse hepatocellular destruction was noted on biopsy of one patient, and another demonstrated massive hepatic necrosis.³³ When used to treat vasculitis, cyclophosphamide has been associated with liver damage when its administration was preceded by azathioprine (AZ).³⁴ Biopsy in three of the four patients in this report showed liver cell necrosis. In two patients, cyclophosphamide had previously been given without antecedent AZ and hepatic injury had not been seen, suggesting an apparent interaction of the two drugs to cause liver cell necrosis.

Ifosfamide is an alkylator and elevations of hepatic enzymes have rarely been reported during therapy. In a study by Bruhl et al.,³⁵ this was seen in only one patient (0.25%) when giving total doses of 300 mg/kg/cycle, fractionated into 60 mg/kg/day. Transient elevations of liver enzymes were noted when Ifosfamide/mesna was given to 97 patients who had malignant solid tumors diagnosed before they were 21 years of age. Patients received 1.6 g per m² ifosfamide daily × 5, given IV over 15 minutes, followed by 400 mg per m² IV mesna at 15 minutes and 4 and 6 hours after ifosfamide.³⁶

The newer alkylating agent bendamustine is approved by the FDA for the treatment of chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. It must be used with caution in patients with mild hepatic impairment. Bendamustine should not be used in patients with moderate (AST or ALT 2.5 to 10 × upper limit of normal [ULN] and total bilirubin 1.5 to 3 × ULN) or severe (total bilirubin > 3 × ULN) hepatic impairment.³⁷

Melphalan is rapidly hydrolyzed in plasma, and approximately 15% is excreted unchanged in the urine. At usual doses, it is not associated with hepatotoxicity, but it does produce transient abnormalities in LFTs at the high doses used in hematopoietic stem cell transplantation (HSCT).^38,39

Chlorambucil, also a nitrogen mustard derivative, was linked to the development of liver damage in 6 patients from an autopsy series of 181 patients with leukemia or lymphoma.⁴⁰ Two patients had postnecrotic cirrhosis, and a third had areas of fibrosis. Variable degrees of centrilobular or periportal liver degeneration and necrosis were seen. Bile thrombi were noted,
usually in central areas, but occasionally midzonal or periportal in location. All six patients were jaundiced, and chlorambucil was implicated as the principal cause in three. All patients in this series had abnormal LFTs. In another reported case, idiosyncratic hepatotoxicity and a rash developed; rechallenge produced the same reaction.⁴¹ This drug must be considered a rare cause of liver dysfunction.

Busulfan is the only alkylsulfonate that is currently used, primarily for the myeloproliferative disorders. After administration, the drug is rapidly cleared from the blood, and almost all labeled busulfan is excreted in the urine as methanesulfonic acid. Hepatic metabolism is apparently not important. In standard doses, busulfan rarely causes hepatic dysfunction but has been linked to at least one case of cholestatic hepatitis.⁴² Another case of cholestasis occurred in a patient in blast crisis who also had leukemic infiltration of the liver.⁴³

Procarbazine hydrochloride, an oral alkylating agent used as a component of chemotherapy regimens for Hodgkin lymphoma, primary CNS lymphoma and high-grade gliomas, is associated with elevated aminotransferase levels.⁴⁴

As a group, the alkylating agents are seldom implicated as hepatotoxins and can usually be given in the face of altered liver function with relative safety. The possible exception to this is cyclophosphamide, which requires adequate liver function for activation to its active metabolites.

The nitrosoureas include carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)], lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)], streptozocin, and the investigational agents chlorozotocin and methyl CCNU. They seem capable of functioning as alkylating and as carbamylating agents. BCNU depletes hepatic stores of glutathione, which may increase the risk of oxidative injury from other sources.⁴⁵ Carmustine (BCNU)-induced liver abnormalities have been reported in up to 26% of patients from 6 to 127 days after treatment.⁴⁶ Elevations of serum aminotransferases, alkaline phosphatase, and/or bilirubin are usually mild and revert to normal over a brief period, although fatalities have been reported. Timing of the toxicity was on average between days 28 and 38. Combinations of carmustine with etoposide have led to severe hepatotoxicity without substantial tumor response.⁴⁷ Toxicity when used as a single agent does not appear to be significant; however, when used in a multiagent regimen such as PCV (procarbazine, CCNU, and vincristine), hepatotoxicity can be seen.⁴⁸

Streptozocin-induced hepatotoxicity is manifest primarily as aminotransferase elevations and occurs in 15% to 67% of patients.^49,50 These changes appear a few days to weeks after treatment and rapidly revert to normal without the production of symptoms or the development of chronic changes.

The antimetabolites that are currently in clinical use include cytosine arabinoside (ara-C), 5-fluorouracil (5-FU), capecitabine, 6-mercaptopurine (6-MP), AZ, 6-thioguanine, fludarabine, pentostatin, clofarabine, gemcitabine, MTX, and pemetrexed. Ara-C is currently the mainstay of treatment of acute myelogenous leukemia (AML) and its variants. It differs from the naturally occurring pyrimidine, cytidine, in that arabinoside replaces ribose as the sugar moiety attached to the pyrimidine base. Intracellularly, ara-C is metabolized in three successive phosphorylation reactions to the triphosphate derivative ara-CTP, which inhibits DNA synthesis by inhibition of DNA polymerase and by misincorporation into the DNA molecule. Its effects are therefore limited to cells that actively synthesize DNA.

In an early series that used cytarabine, abnormal LFTs were reported in 37 of 85 leukemic patients,⁵¹ but many had preexisting liver function abnormalities before treatment, confounding factors such as sepsis or hemolysis, or resolution of biochemical abnormalities despite continuation of therapy. No definite evidence of hepatotoxicity could be found. Ever since, establishing the drug as a hepatotoxin has been especially difficult, because patients with leukemia have frequently received transfusions, are subject to infections, are on multiple medications, and are not candidates for liver biopsy because of their usual thrombocytopenia. In patients in whom biopsies have been possible, drug-induced intrahepatic cholestasis has been demonstrated.^52,53 Although abnormal liver tests developed in 24 of 27 leukemic patients who were given high-dose cytarabine by continuous infusion over 72 hours, the effects are reversible and not dose limiting.^54,55,56

Fludarabine is a purine antimetabolite used to treat lymphoma. Reversible elevation of the serum transaminases to two to three times normal has been described.^57,58

Cladribine is used in hairy cell leukemia. Hepatic toxicity has been reported in a phase I study where three patients developed elevated serum bilirubin levels, as high as 6 mg per dl. One patient who died developed severe transaminitis and an increased alkaline phosphatase.⁶⁸ There is a report of 197 patients who received cladribine as second-line therapy after failing α-interferon with a 19% incidence of hepatic enzyme elevations.

Pentostatin has a similar spectrum of activity to cladribine. Rarely elevated transaminases have been reported and hepatotoxicity appears uncommon.^59,60

Clofarabine, a purine (deoxyadenosine) nucleoside analog, is metabolized to clofarabine 5′-triphosphate. It is approved by the FDA for the treatment of pediatric patients between the ages of 1 and 21 for relapsed or refractory acute lymphoblastic leukemia (ALL) after at least two prior regimens. The dose-limiting toxicity of transient hepatotoxicity was noted in a phase I study of 32 patients with acute leukemia when administered a maximum tolerated dose of 40 mg/m²/day given as a 1-hour infusion daily for 5 days.^61,62

5-FU is used in the treatment of breast cancer, head and neck cancer, lung cancer, and gastrointestinal cancers. When given intravenously, it is metabolized by anabolism in tissues to its active form, 5-fluorodeoxyuridine monophosphate, which inhibits thymidylate synthetase. The drug is also catabolized, primarily in the liver, as dihydrouracil dehydrogenase reduces the pyrimidine ring. The reduced compound is then cleaved to α-fluoro-β-alanine, ammonia, urea, and carbon dioxide, as in the degradation of uracil. The toxicity and the antitumor effect are potentiated if catabolism is blocked by dihydrouracil dehydrogenase inhibition. Approximately 15% of the administered drug is excreted in the urine unchanged. Although the liver plays a key role in its catabolism, 5-FU has not been reported to cause liver damage when given orally, and only rare reports of possible hepatotoxicity have been noted when the drug is given intravenously.⁶³

When the 5-FU metabolite fluorodeoxyuridine (FUDR, floxuridine) is given intraarterially by implantable pump for hepatic metastases from colorectal carcinoma, new toxicities become apparent.⁶⁴ Two major pictures may be seen: (1) chemical hepatitis with rises in aminotransferases, alkaline phosphatase, and serum bilirubin; and (2) stricture of the intrahepatic or extrahepatic bile ducts, accompanied by elevated alkaline phosphatase and bilirubin levels.^65,66,67 Toxicity appears to be time and dose dependent. With rare exceptions, the hepatitis picture improves with the temporary cessation of chemotherapy, but the development of secondary sclerosing cholangitis is irreversible.^68,69 Two patterns of sclerosis may be seen, a diffuse pattern and the diffuse pattern plus short segments of tight stricture, usually located in the proximal bile ducts.⁷⁰ Compared with conventional intravenous (IV) 5-FU therapy, intraarterial fluorodeoxyuridine offers a higher response rate but at the cost of increased liver toxicity.^71,72

Capecitabine is the prodrug for 5-FU and also has had reports of hepatotoxicity. According to the product information, an elevated serum bilirubin occurred in 22% of 162 patients with metastatic breast cancer and in 48% of 596 patients with metastatic colorectal cancer in clinical trials. Out of 875 patients who were evaluated for toxicity in clinical trials, grade 3 hyperbilirubinemia occurred in 15.2% of patients and grade 4 occurred in 3.9%. Grade 3 or 4 hyperbilirubinemia occurred in 22.8% of patients with hepatic metastases at baseline (n = 566) and 12.3% of patients without hepatic metastases (n = 309). When capecitabine was used as first-line therapy for metastatic colorectal cancer in 596 patients, the incidence of grade 3 or 4 hyperbilirubinemia was similar to the capecitabine monotherapy overall clinical trial safety database.⁷³ According to the product information, administration of capecitabine should be immediately interrupted if hyperbilirubinemia of grade 2 (1.5 × ULN), 3, or 4 occurs until the hyperbilirubinemia resolves or decreases in intensity to grade 1. Patients with mild to moderate hepatic dysfunction due to liver metastases should be carefully monitored.⁷⁴

Gemcitabine is a cytosine analog used in a variety of treatment settings. Gemcitabine, used in breast, ovarian, non-small cell lung cancer (NSCLC), and pancreatic cancer, is a fluorine substituted deoxycytidine analog with broad-spectrum antitumor activity. It is commonly associated with elevated levels of transaminases, but this is seldom of clinical significance. Three cases of fatal cholestatic hepatotoxicity have been reported and current recommendations are for dose reduction in patients with an elevated serum bilirubin. An elevated bilirubin level of >1.6 mg per dl requires that the dose be started at 800 mg per m² and escalated only if tolerated.^75,76 In clinical trials, gemcitabine was associated with transient elevations of one or both serum transaminases in approximately 70% of patients, but there was no evidence of increasing hepatic toxicity either with longer duration of exposure to gemcitabine or with greater total cumulative dose. Serious hepatotoxicity, including liver failure and death, has been reported in patients receiving gemcitabine alone or in combination with other potentially hepatotoxic drugs.^75,77,78 Gemcitabine should be used with caution in patients with preexisting hepatic insufficiency, concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis, which may lead to exacerbation of the underlying hepatic insufficiency. When serum bilirubin is >1.6 g per dl, a starting dose of 800 mg per m² is used.⁶

The purine analog 6-MP is used chiefly in the maintenance therapy of ALL. When activated by hypoxanthine guanine phosphoribosyltransferase to the monophosphate nucleotide, the drug inhibits de novo purine synthesis. Phosphorylation to the triphosphate permits incorporation into DNA. The drug is metabolized by xanthine oxidase to 6-thiouric acid. Hepatotoxicity induced by 6-MP may occur in a variety of settings, especially when the dose of the drug exceeds the usual daily dose of 2 mg per kg, and may present as either hepatocellular or cholestatic liver disease.^79,80 Preclinical animal studies noted the development of hepatic necrosis in mice and rats, and shortly after its introduction, 6-MP was incriminated in
the development of jaundice.^81,82 Biopsy revealed bland cholestasis, with minimal hepatic necrosis but significant cytologic atypia and disorganized hepatic cords, a picture confirmed on multiple occasions.^83,84 Stopping the drug was followed by resolution of the jaundice. 6-MP may also produce a hepatocellular injury pattern.⁸⁰ Serum bilirubin levels are usually between 3 and 7 mg per dl, with moderate elevations in aminotransferases and alkaline phosphatase. Most episodes of jaundice occur >30 days after the initiation of therapy. Changing the route of administration from oral to IV did not alter the production of hepatotoxicity, as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values above 150 U per L developed in 14 of 40 patients.⁸⁵ It has been suggested that the drug has a direct toxic effect, because rechallenge after its discontinuation does not necessarily shorten the latent period, and systemic manifestations of hypersensitivity, such as rash, arthralgias, and eosinophilia, are not usually present.⁸⁰ However, in a series of 396 patients who were treated for an average of 60 months with 1.5 mg/kg/day 6-MP for refractory inflammatory bowel disease, hepatitis occurred in only one patient, and liver biopsy suggested hypersensitivity.⁸⁶

AZ, the nitroimidazole derivative of 6-MP, is used for the prevention of solid organ transplant rejection and in the management of patients with autoimmune diseases such as autoimmune hepatitis and inflammatory bowel disease.⁸⁷ Like 6-MP, AZ can induce liver toxicity,⁸⁸ but with less frequency. Hepatotoxicity is seen chemically as increased serum bilirubin and alkaline phosphatase levels with moderate elevations in aminotransferases and histologically as cholestasis with variable parenchymal cell necrosis. Most reports of AZ hepatic toxicity have been in the renal transplant population, which has had a high incidence of viral hepatitis, causing some observers to doubt the hepatotoxic potential of AZ. In some renal transplant patients, liver abnormalities progressed when AZ was stopped; in others, they improved although the drug was continued or the patient was rechallenged. A prospective study of patients with psoriasis who were receiving AZ did not show deterioration of liver function.⁸⁹ AZ is probably hepatotoxic, but compared with 6-MP, its effects are less frequent, milder, and less dose dependent. It has been speculated that patients in whom hepatotoxicity develops are those who convert AZ into 6-MP at an unusually rapid rate,⁸⁸ an example of host metabolic idiosyncrasy. A prospective study of psoriatic patients who received AZ did not reveal deterioration of LFTs,⁸⁹ but a retrospective review of patients with neuromuscular disease found a 9% incidence of hepatotoxicity.⁹⁰ In another report, 3 of 25 patients with rheumatoid arthritis (RA) developed fever, chills, rash, and hepatotoxicity.⁹¹ AZ toxicity documented by histopathology and rechallenge has also been reported. In a patient who received high doses of AZ for an autoimmune neurologic disorder, rapidly progressive and fatal sclerosing hepatitis developed.⁹²

In several renal transplant patients, hepatic VOD (HVOD) has developed after immunosuppressive therapy with AZ.^93,94 The clinical presentation varied from a mild virus-like syndrome to rapidly fulminant liver failure and death, with severe progressive portal hypertension in some patients. An association has been reported with cytomegalovirus infections, but not with AZ dose, type or duration of transplant, or type of underlying kidney disease.⁹⁴