Exemestane and the Liver

Exemestane is a steroidal molecule, and this often raises a question: doesn't it harm the liver the same way oral anabolic steroids do? The answer requires examining the chemistry, the metabolism, and the real clinical data. The editorial team has gathered what is known about exemestane's interaction with the liver from the drug's prescribing information, the LiverTox database, and research studies.

A steroid, but not a "classic" hepatotoxin

Steroid liver toxicity is most often discussed in the context of oral anabolics - methandienone, stanozolol, oxandrolone. Their common feature is the 17-alpha-alkyl group, which protects the molecule from breakdown during first pass through the liver and is at the same time associated with cholestasis, peliosis, and liver tumors.

Exemestane also has a steroidal skeleton: it is a derivative of androstenedione with a double bond at position 1 and a methylene group at position 6. However, it has no 17-alpha-alkyl group. At position 17 there is a keto group, as in natural androstenedione.

Therefore the mechanisms by which oral anabolic steroids damage the liver do not apply directly to exemestane. A steroidal structure in itself does not make a substance hepatotoxic: hepatotoxicity is determined by specific chemical groups and the way a substance is metabolized.

For exemestane something else matters more: the liver is the main organ of its conversion and elimination. So the condition of the liver affects the drug more than the drug affects the liver.

Exemestane's path through the liver

Exemestane is rapidly absorbed from the intestine, and fatty food, according to the Aromasin prescribing information, increases its absorption. That is why in studies and in the prescribing information the drug is taken after meals. From there, practically all of the substance reaches the liver, where it is intensively metabolized.

The prescribing information indicates two main conversion pathways. The first is oxidation of the methylene group involving cytochrome CYP3A4. The second is reduction of the 17-keto group by aldoketoreductases, forming 17-hydroexemestane, a metabolite with weak androgenic activity. The metabolites are then conjugated and excreted in urine and feces in roughly equal proportions.

The half-life of exemestane is about a day. However, because of irreversible binding to aromatase, the duration of its action is determined not only by blood concentration but also by the rate of synthesis of new enzyme molecules. This distinguishes it from reversible inhibitors.

Researchers have also noted genetic variability in the enzymes that conjugate 17-hydroexemestane. This may partly explain differences in metabolite concentrations between individuals, although the clinical significance of these differences is still being clarified.

Hepatic impairment and dosing

Because exemestane is eliminated mainly through hepatic metabolism, its concentration rises when the liver is impaired. According to the pharmacokinetic studies cited in the prescribing information, in people with moderate and severe hepatic impairment systemic exposure to exemestane was several times higher than in healthy volunteers.

Despite this, the manufacturer does not recommend a dose adjustment in hepatic impairment. The rationale is the drug's wide therapeutic range: clinical studies used doses higher than standard without a substantial increase in toxicity. This distinguishes exemestane from letrozole, for which a dose reduction is provided in severe hepatic impairment.

Still, the absence of a formal adjustment does not mean an absence of attention. In patients with cirrhosis or other severe liver diseases, higher concentrations may intensify systemic side effects, and liver disease itself affects the metabolism of hormones and lipids.

In clinical practice the oncologist coordinates treatment with a hepatologist, weighs the expected benefit, and monitors well-being and laboratory values. This also applies to patients with liver metastases, in whom deviations in liver tests are often related to the disease itself.

Hepatotoxicity in clinical data

The LiverTox database of the US National Institutes of Health describes exemestane as a drug with a low risk of liver injury. In clinical studies a small proportion of patients showed a moderate rise in liver enzymes, usually asymptomatic and not requiring discontinuation.

The Aromasin prescribing information mentions elevations of alkaline phosphatase, bilirubin, and transaminases among the laboratory changes recorded in studies. Some of these changes were attributed to disease progression, in particular to liver and bone metastases, rather than to a direct action of the drug.

Clinically significant liver injury associated with exemestane has been described only in isolated reports. Such cases were predominantly cholestatic in character and resolved after the drug was stopped.

• Moderate asymptomatic enzyme elevation - infrequent.
• Elevated alkaline phosphatase - may reflect bone involvement rather than the liver.
• Clinical hepatitis or cholestasis - isolated reports.

In large studies such as IES or MAP.3, liver complications were not among the main safety concerns. Hot flashes, joint pain, and bone loss were discussed far more often.

Interactions and practical monitoring

Because exemestane is metabolized with the involvement of CYP3A4, strong inducers of this enzyme - rifampicin, some anticonvulsants, St. John's wort - lower its concentration. For such cases the prescribing information allows for a possible dose increase, but only a doctor makes that decision.

CYP3A4 inhibitors, according to the manufacturer, do not noticeably change the pharmacokinetics of exemestane, which is explained by the presence of an alternative metabolic pathway through aldoketoreductases. Exemestane itself probably does not substantially inhibit the main cytochromes.

Guidelines do not provide for specific liver monitoring in all patients. In practice, a biochemical blood test is done before treatment begins, and thereafter liver tests are checked as indicated: with symptoms, liver disease, or concurrent use of hepatotoxic drugs.

In a non-medical context, where exemestane is combined with oral anabolic steroids, the main burden on the liver is created precisely by the latter. Such a combination has no evidence base for safety, and aromatase inhibitors are banned by WADA.

Editorial conclusions

Exemestane has a steroidal structure but contains no 17-alpha-alkyl group, so the classic mechanisms of steroidal hepatotoxicity do not apply to it.

For exemestane the liver is above all an organ of metabolism. When it is impaired, exposure to the drug rises several times over, but thanks to the wide therapeutic range the manufacturer does not require a dose adjustment.

Direct liver injury is rare, and changes in laboratory values are often explained by the disease itself. A sensible approach is baseline biochemistry and monitoring as indicated.

The editorial team also recommends our materials "Letrozole and the Liver," "Exemestane in Women: Medical Indications," and "The History of Exemestane's Creation."

References

1. Pfizer. Aromasin (exemestane) tablets: prescribing information. U.S. Food and Drug Administration.
2. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Exemestane. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–.
3. Lombardi P. Exemestane, a new steroidal aromatase inhibitor of clinical relevance. Biochim Biophys Acta. 2002;1587(2–3):326–337.
4. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081–1092.
5. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381–2391.
6. Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341–375.