Does Cyclobenzaprine (Flexeril) affect the liver?

From the Guidelines

Cyclobenzaprine (Flexeril) can potentially affect the liver, particularly in individuals with pre-existing liver disease, due to its extensive first-pass metabolism in the liver. The medication is primarily metabolized by the liver through the cytochrome P450 system, specifically the CYP3A4, CYP1A2, and CYP2D6 enzymes 1. This process may lead to higher blood levels of the medication in patients with compromised liver function, potentially increasing side effects. However, serious liver problems are uncommon with normal use of Flexeril. Patients taking Flexeril should be aware of warning signs of liver problems such as yellowing of the skin or eyes, dark urine, persistent nausea, upper right abdominal pain, or unusual fatigue, which should prompt immediate medical attention. The standard dosage of Flexeril is typically 5-10 mg three times daily, with treatment generally limited to 2-3 weeks to minimize side effects. Regular liver function monitoring is not routinely required for short-term use in healthy individuals but may be recommended for those with pre-existing liver conditions. It is essential to note that the evidence provided does not directly address the liver effects of cyclobenzaprine, but its metabolism and potential for increased side effects in liver disease suggest caution 1. Key points to consider when prescribing Flexeril include:

• Monitoring for signs of liver problems
• Dose adjustments in patients with liver disease
• Limiting treatment duration to minimize side effects
• Awareness of the medication's metabolism and potential for increased side effects in compromised liver function.

From the FDA Drug Label

Impaired Hepatic Function The plasma concentration of cyclobenzaprine is increased in patients with hepatic impairment In rats treated with cyclobenzaprine hydrochloride for up to 67 weeks at doses of approximately 5 to 40 times the maximum recommended human dose, pale, sometimes enlarged, livers were noted and there was a dose-related hepatocyte vacuolation with lipidosis

Cyclobenzaprine affects the liver. The drug's plasma concentration is increased in patients with hepatic impairment, and it should be used with caution in subjects with mild hepatic impairment. Additionally, animal studies have shown that cyclobenzaprine can cause liver changes, including hepatocyte vacuolation with lipidosis, at high doses 2.

From the Research

Cyclobenzaprine and Liver Effects

• The study 3 investigated the metabolism of cyclobenzaprine in human liver microsomes and found that cytochrome P4503A4 and 1A2 are primarily responsible for cyclobenzaprine metabolism, with cytochrome P4502D6 playing a minor role.
• Another study 4 mentioned that dantrolene, and to a lesser degree chlorzoxazone, have been associated with rare serious hepatotoxicity, but did not provide information on cyclobenzaprine's effects on the liver.
• A study on dose adjustment in patients with liver disease 5 discussed the importance of considering hepatic extraction and bioavailability when administering drugs to patients with liver disease, but did not specifically address cyclobenzaprine.
• Studies 6 and 7 focused on the pharmacokinetics and efficacy of cyclobenzaprine in various populations, but did not provide information on its effects on the liver.

Hepatic Metabolism of Cyclobenzaprine

• The primary study 3 on cyclobenzaprine's metabolism in human liver microsomes found that cytochrome P4503A4 and 1A2 are the main enzymes involved in its metabolism.
• This suggests that cyclobenzaprine may be affected by liver function, particularly in patients with impaired cytochrome P4503A4 or 1A2 activity.
• However, the study 3 did not investigate the potential for cyclobenzaprine to cause liver damage or affect liver function.

Clinical Implications

• The lack of direct evidence on cyclobenzaprine's effects on the liver makes it difficult to draw conclusions about its potential hepatotoxicity.
• However, the fact that cyclobenzaprine is metabolized by cytochrome P450 enzymes in the liver suggests that patients with liver disease or impaired liver function may require dose adjustments or closer monitoring.
• Further studies are needed to fully understand the relationship between cyclobenzaprine and liver function, as well as its potential for hepatotoxicity 3, 4.