The proposed hydroxy acid metabolite of etoposide, formed by opening of the lactone ring, has been detected in human urine, but only at low concentrations, accounting for 0.2-2.2% of the administered dose.
The major urinary metabolite of etoposide in humans is reported to be the glucuronide conjugate. Although urinary glucuronide and/or sulfate conjugates were reported to account for 5-22% of an intravenous dose of etoposide, other studies suggest that the glucuronide predominates. Etoposide glucuronide in the urine of treated patients accounted for 8-17% of a dose of 0.5-3.5 g/sq m etoposide and 29% of a dose of 100-800 mg/sq m etoposide, with no other metabolites other than etoposide glucuronide detected in the latter study. In patients with renal or liver impairment given somewhat lower doses of 70-150 mg/sq m, 3-17% of the dose was excreted in the urine within 72 hr as etoposide glucuronide.
Etoposide appears to be metabolized principally at the D ring to produce the resulting hydroxy acid (probably the trans-hydroxy acid); this metabolite appears to be pharmacologically inactive. The picrolactone isomer of etoposide has been detected in two concentrations in the plasma and urine of some patients but not in others. The aglycone of etoposide and/or its conjugates have not been detected to date in patients receiving the drug. In vitro, the picrolactone isomer and aglycone of etoposide have minimal cytotoxic activity.
Generally, few or no etoposide metabolites have been detected in plasma. Etoposide is administered as the trans-lactone, but cis-etoposide can also be detected in human urine. This might be a storage phenomenon, since isomerization sometimes occurs during freezing of plasma samples under slightly basic conditions. The cis isomer accounts for < 1% of the dose. The catechol metabolite has also been reported in patients receiving 600 mg/sq m etoposide, with an AUC of around 2.5% that of etoposide. In patients given 90 mg/sq m etoposide, the catechol metabolite represented 1.4-7.1% of the urinary etoposide and < 2% of the administered dose.
In rat liver homogenates, liver microsomes and in rats in vivo, etoposide was extensively metabolized to only one major metabolite, which was not formally identified. In perfused isolated rat liver incubated with etoposide, the total recovery in bile was 60-85%, with roughly equal amounts of etoposide and two glucuronide metabolites, confirmed as glucuronide species by liquid chromatography and mass spectrometry. After intravenous injection of 3(H)etoposide to rabbits, the total urinary excretion of radiolabel was 30% after five days, with very little thereafter. A single glucuronide metabolite was identified in rabbit urine, which was present in larger amounts than etoposide. No hydroxy acid was identified in either species.
Chemotherapy with etoposide or teniposide in combination with other agents is associated with serum enzyme elevations in 5% to more than 50% of patients, depending upon the dose and other agents used. The ALT elevations are usually asymptomatic and transient and may resolve without dose modification. In many instances, it is difficult to attribute the liver test abnormalities to etoposide or teniposide because of the exposure to other potentially hepatotoxic agents. Rare instances of clinically apparent liver injury have been reported in patients receiving etoposide, but the time to onset and pattern of injury has varied greatly. Onset can be as short as 1 to as long as 5 months after initiation of therapy. Some published cases of liver injury after regimens of chemotherapy that have included etoposide appear to represent sinusoidal obstruction syndrome. These cases have usually followed etoposide therapy in combination with an alkylating agent or total body irradiation. In addition, etoposide has been linked to cases of acute hepatitis arising after 1 to 5 months of treatment, which have generally been self-limiting, but occasionally severe. The role of etoposide in causing injury was not always clear. The pattern of serum enzyme elevation in reported cases has been hepatocellular. Immunoallergic features (rash, fever, eosinophilia) and autoantibodies were absent. The liver histology of etoposide hepatotoxicity has not been well characterized. The hepatotoxicity of teniposide has been less well defined than that of etoposide, probably because it has had limited use.
Likelihood score, etoposide: C (probable cause of clinically apparent liver injury).
Likelihood score, teniposide: E* (unproven but suspected cause of clinically apparent liver injury).
Evaluation: There is limited evidence in humans for the carcinogenicity of etoposide. There is sufficient evidence in humans for the carcinogenicity of etoposide given in combination with cisplatin and bleomycin. There is inadequate evidence in experimental animals for the carcinogenicity of etoposide. Overall evaluation: Etoposide is probably carcinogenic to humans (Group 2A). In reaching this evaluation, the Working Group noted that etoposide causes distinctive cytogenetic lesions in leukemic cells that can be readily distinguished from those induced by alkylating agents. The short latency of these leukemias contrasts with that of leukemia induced by alkylating agents. Potent protein masked DNA breakage and clastogenic effects occur in human cells in vitro and animal cells in vivo. Etoposide in combination with cisplatin or bleomycin is carcinogenic to humans.
Excretion of etoposide in breast milk was demonstrated in a woman with acute promyelocytic leukemia receiving daily doses of 80 mg/sq m (route not stated). Peak concentrations of 0.6 to 0.8 ug/mL were measured immediately after dosing but had decreased to undetectable levels by 24 hr.
Thirty minutes after intravenous administration of etoposide to rats, the highest concentrations were found in the liver, kidneys and small intestine. By 24 hr after the dose, the tissue concentrations were negligible.
After intravenous infusion (5 min) of etoposide phosphate to beagle dogs at doses of 57-461 mg/sq m, a dose-proportional increase was seen in the maximal plasma concentration and AUC for etoposide. The total plasma clearance rate (342-435 mL/min per sq m) and the distribution volume (22-27 L/sq m) were not dose-dependent. The peak plasma concentration occurred at the end of the infusion of etoposide phosphate, indicating rapid conversion of the pro-drug to etoposide.
Less than 4% of a dose was recovered in the bile after 48 hr in patients with biliary drainage tubes. The fecal recovery of radiolabel after intravenous administration of 3(H)etoposide (130-290 mg/sq m) was variable, representing 0-16% of dose, but the collections were known to be incomplete because of fecal retention and other difficulties associated with the poor general condition of many of the patients). In a study reported as an abstract in four patients with small-cell lung cancer given 14(C)-glucopyranoside etoposide, 56% of the radiolabel was recovered in urine and 44% in feces over five days, for a total recovery of 100 +/- 6%.
