2-hydroxyFlutamide is an androgen receptor (AR) inhibitor [1].

The androgen receptor has been implicated in the development and progression of prostate cancer. AR is expressed in many androgen-independent or hormone refractory prostate cancers and is maintained throughout prostate cancer progression. Inactivation of AR may delay prostate cancer progression [2].

2-hydroxyFlutamide is the major metabolite of flutamide generated during the metabolism of the non-steroidal antiandrogen flutamide by CYP1A2 and CYP3A4. Flutamide is an antiandrogenic drug which has been widely used for treatment of prostate cancer. 2-hydroxyflutamide could inhibit flutamide metabolism. In cells, increased conversion of flutamide to 2-hydroxyflutamide or accumulation of 2-hydroxyflutamide may result in the anomalous responses to flutamide, which can be observed in some advanced prostate cancers [3]. 2-hydroxy flutamide blocked the expression of AR target genes and prevented androgen-dependent stabilization of the AR [1]. 2-hydroxyFlutamide was a more powerful antiandrogen in vivo, with higher binding affinity for the AR than flutamide. In humans, hydroxyflutamide exhibited an elimination halflife of about 8 h [3].

References:[1] Kolvenbag G, Furr B J A, Blackledge G R P. Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity[J]. Prostate cancer and prostatic diseases, 1998, 1: 307-314.[2] Heinlein C A, Chang C. Androgen receptor in prostate cancer[J]. Endocrine reviews, 2004, 25(2): 276-308.[3] Shet M S, McPhaul M, Fisher C W, et al. Metabolism of the antiandrogenic drug (Flutamide) by human CYP1A2[J]. Drug metabolism and disposition, 1997, 25(11): 1298-1303.[4] Gao W, Kim J, Dalton J T. Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands[J]. Pharmaceutical research, 2006, 23(8): 1641-1658.