4hydroxyflutamide

4-hydroxyflutamide is the major active metabolite of flutamide, a nonsteroidal antiandrogen used in the treatment of androgen-dependent conditions such as prostate cancer. It is formed in the liver by hydroxylation of flutamide at the 4-position of the aromatic ring, a reaction carried out by hepatic cytochrome P450 enzymes. The metabolite contributes to the pharmacologic activity of flutamide and, in some assessments, shows similar or greater affinity for the androgen receptor than the parent drug, enhancing antiandrogen effects.

As an antiandrogen, 4-hydroxyflutamide antagonizes the androgen receptor, blocking signaling by dihydrotestosterone and testosterone. This AR blockade helps reduce androgen-driven tumor growth in prostate cancer and can influence the clinical response to flutamide therapy. The relative potency of the metabolite compared with flutamide can vary between studies, but it is widely considered a key mediator of the drug’s activity.

Pharmacokinetically, 4-hydroxyflutamide is further metabolized, including glucuronidation, and is excreted in urine and feces. It often exhibits different pharmacokinetic properties from flutamide, including a distinct half-life, which can affect onset and duration of antiandrogen effects and potential drug interactions.

Clinical considerations include the recognition that individual differences in hepatic metabolism can influence exposure to 4-hydroxyflutamide and, consequently, treatment response and toxicity. Like flutamide, the metabolite carries a risk of hepatotoxicity, so monitoring liver function is advised during therapy. While not typically administered on its own, 4-hydroxyflutamide is an important contributor to the pharmacology of flutamide therapy.