Toremifene and the liver

The liver is the main organ toremifene passes through: here it is converted into active metabolites, and here the most common laboratory abnormalities arise. Our editors examined exactly how the drug is metabolized, how real the risk of toxic liver injury is, how toremifene differs from tamoxifen and which tests make sense.

The path of toremifene through the liver

Toremifene is a selective estrogen receptor modulator (SERM) of the triphenylethylene group, chemically close to tamoxifen: it differs from it only by a chlorine atom in the side chain. The drug is registered under the name Fareston for the treatment of metastatic hormone-sensitive breast cancer in postmenopausal women. It is well absorbed from the intestine and binds almost completely to plasma proteins, primarily albumin.

The main conversion step takes place in hepatocytes with the participation of the cytochrome enzyme CYP3A4. It removes a methyl group, forming N-desmethyltoremifene — a metabolite with similar antiestrogenic activity, whose blood concentration during long-term use even exceeds that of the parent compound. The metabolites then undergo hydroxylation and conjugation and are eliminated mainly with bile and feces rather than urine.

The half-life of toremifene is long — on average about five days, and that of the N-desmethyl metabolite is even longer. Therefore a steady blood concentration is established only after several weeks, and the drug likewise disappears slowly after discontinuation. For the liver this means a prolonged rather than short-term load.

This dependence on the liver has two practical consequences. First, any decline in its function (cirrhosis, severe hepatitis) slows elimination of the drug and raises its level. Second, medicines that inhibit or stimulate CYP3A4 markedly change the concentration of toremifene — this matters in view of its effect on the QT interval.

Which changes in liver markers have been described

In clinical studies in women with breast cancer, the most common “liver” finding was a moderate rise in transaminases (ALT, AST), alkaline phosphatase and gamma-glutamyltransferase. Such changes were usually asymptomatic and detected only in tests. Importantly, in this group of patients some abnormalities are related not to the drug but to metastases in the liver or bones.

The LiverTox database of the US National Institutes of Health classifies toremifene among drugs that cause elevated liver enzymes in a minority of patients, while clinically evident liver injury with jaundice has been described only in isolated cases. For comparison: tamoxifen is associated with both steatosis and rare cases of severe hepatitis — the documentation for toremifene is far more modest, in part because it is used less often.

A separate question is fatty liver disease. For tamoxifen, the development of steatosis in some women during adjuvant therapy is well documented. For toremifene there are fewer direct large-scale data, but given the close chemical structure and the shared mechanism in the liver, our editors consider it reasonable to expect a similar, though perhaps less pronounced, effect.

Another mechanism is the effect of SERMs on protein synthesis in the liver. Toremifene, like other drugs of its class, shows partial estrogenic activity in the liver: it raises the level of sex hormone-binding globulin (SHBG) and lowers LDL. This is not toxicity but a pharmacological effect, yet it should be taken into account when interpreting tests.

Toremifene and tamoxifen: the difference for the liver

Historically, toremifene was created specifically as a “safer for the liver” analog of tamoxifen. In preclinical studies tamoxifen at high doses caused liver tumors in rats: its metabolites form covalent compounds with DNA (so-called DNA adducts). In similar models toremifene formed far fewer such adducts and showed no hepatocarcinogenic effect in rats.

At the same time it is important not to overstate this advantage. In humans the risk of liver cancer from tamoxifen at therapeutic doses is not confirmed, so the difference between the drugs is mainly of preclinical significance. In clinical comparisons, in particular the meta-analysis by Pyrhonen and colleagues (1999), the efficacy and overall tolerability profile of the two drugs in breast cancer proved similar.

Both drugs are metabolized with the participation of liver cytochromes, but differently: tamoxifen depends largely on CYP2D6 for the formation of endoxifen, whereas toremifene depends mainly on CYP3A4. Therefore genetic variants of CYP2D6, important for tamoxifen, matter less for toremifene, while interactions with CYP3A4 inhibitors become more critical.

In the sports community toremifene is sometimes presented as a “gentler for the liver” option. Our editors point out: such claims rest on preclinical data and the experience of oncology patients, not on studies in healthy people who combine SERMs with other substances, in particular hepatotoxic oral steroids.

Who is in the higher-risk group

The Fareston prescribing information does not recommend using the drug in severe hepatic insufficiency and requires caution in impaired liver function, since elimination of toremifene is slowed in this case. The risk is also higher in several groups of people:

• people with pre-existing liver disease — viral hepatitis, alcoholic injury, non-alcoholic fatty liver disease;
• those who consume alcohol regularly or in large amounts;
• patients who simultaneously take CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, some antiviral drugs) — the level of toremifene rises;
• people who use other potentially hepatotoxic substances, in particular 17-alpha-alkylated anabolic steroids;
• patients with obesity and metabolic syndrome, in whom steatosis occurs more often to begin with.

The combination with 17-alpha-alkylated steroids deserves separate attention. Such substances are themselves capable of causing cholestasis, hepatic peliosis and adenomas, as summarized in the scientific statement of the Endocrine Society (Pope et al., 2014). Adding another drug with hepatic metabolism complicates both the load and the interpretation of tests.

Reverse interactions are no less important. CYP3A4 inducers — phenytoin, carbamazepine, rifampicin, St. John’s wort — accelerate the breakdown of toremifene and can reduce its efficacy. Grapefruit juice, on the contrary, moderately inhibits this enzyme in the intestine.

Finally, the QT interval should be kept in mind. Toremifene carries a warning in its prescribing information about QT prolongation, and any rise in the drug’s concentration due to poor liver function or an interaction increases this risk. Thus the hepatic safety of toremifene is closely linked to cardiac safety.

Monitoring and warning symptoms

In medical practice a doctor usually assesses liver function before starting treatment and periodically during it. The minimum set is ALT, AST, alkaline phosphatase, GGT, total and direct bilirubin. In the presence of risk factors, liver ultrasound to assess steatosis may be advisable.

Results should be interpreted over time. A single small rise in transaminases after intense training may be a consequence of muscle damage rather than the liver: AST and even ALT are partly contained in muscle tissue. Therefore before a test it is worth refraining from heavy exercise for a few days and, if needed, adding creatine kinase.

Regardless of tests, there are symptoms that call for immediate medical attention: yellowing of the skin or the whites of the eyes, dark urine, pale stools, persistent nausea, pain in the right upper abdomen, itching of the skin without a rash, unusual weakness.

The “hepatoprotectors” popular among athletes are not a substitute for monitoring. For most of them the evidence base for preventing drug-induced liver injury is limited, and they do not neutralize the drug’s effect on CYP3A4 or on QT.

Editorial conclusions

Toremifene depends entirely on the liver: it is converted by CYP3A4, and the metabolites are eliminated with bile. Because of the long half-life, the load on the liver is not short-term.

A moderate rise in liver enzymes is a described but mostly asymptomatic finding; severe liver injury is rare. The preclinical advantage over tamoxifen regarding DNA adducts is real, but its clinical significance for humans is not proven.

The main risks arise with pre-existing liver disease, alcohol, interactions with CYP3A4 inhibitors and combination with hepatotoxic substances. Monitoring liver markers and attention to symptoms are a mandatory part of any treatment.

We also recommend reading our materials “Mechanism of action of toremifene,” “Contraindications and interactions of toremifene” and “Tests during toremifene use.”

References

1. Fareston (toremifene citrate) tablets. Prescribing information. U.S. Food and Drug Administration.
2. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Toremifene. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases.
3. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Tamoxifen. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases.
4. Pyrhönen S, Ellmén J, Vuorinen J, et al. Meta-analysis of trials comparing toremifene with tamoxifen and factors predicting outcome of antiestrogen therapy in postmenopausal women with breast cancer. Breast Cancer Res Treat. 1999;56(2):133–143.
5. 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.
6. World Anti-Doping Agency. The World Anti-Doping Code: International Standard. Prohibited List. Montreal: WADA (актуальна редакція).