title: Pharmacokinetics and metabolism of nilutamide.
abstract: Data are available on the pharmacokinetics and metabolism of nilutamide in the rat, dog, and human (normal volunteers and patients with advanced prostatic carcinoma). Studies using 14Carbon-nilutamide, radioimmunoassay, and high-performance liquid chromatography (HPLC) are reviewed. In the rat, bioavailability by the oral route was complete. The majority of the plasma radioactivity was unchanged nilutamide up to six hours, t1/2 was seven hours, and clearance was 150 mL/hour/kg body weight. Metabolism studies identified 6 urinary metabolites. The major metabolites result from reduction of the nitro group initially to an hydroxylamine (17%) and then to a primary amino (26%) group. In normal volunteers the compound was rapidly absorbed, displayed linear kinetics over a dose range of 100-300 mg, and declined slowly in plasma with a terminal phase t1/2 of forty-three to forty-nine hours. In studies in 12 patients with advanced (Stage D) prostatic carcinoma, single-dose kinetics after 14C-nilutamide and kinetics with repetitive twice-daily dosing of two to seven weeks were measured. Terminal phase plasma t1/2 of unchanged nilutamide was 56 +/- 19 hours and of total radioactivity 87 +/- 27 hours (mean +/- SD). Area under the curve of plasma radioactivity was 23 to 38 percent unchanged nilutamide. Urinary excretion of radioactivity was slow and incomplete because the collection time was not long enough in regard to t1/2 (mean after 5 days, 62 +/- 10%) and consisted almost entirely of metabolites. Steady-state plasma levels of nilutamide were reached in about two weeks. It can be concluded that in humans, unlike other species, plasma decay of nilutamide is very slow. Elimination is almost exclusively by metabolism. Single-daily dosing is appropriate. Hepatic impairment could be expected to prolong plasma decay; renal impairment is likely to have little effect.
authors.affiliation: Department of Medicine, Roswell Park Memorial Institute, Buffalo, New York.
authors.forename: P J
authors.initials: PJ
authors.lastname: Creaven
authors.forename: L
authors.initials: L
authors.lastname: Pendyala
authors.forename: D
authors.initials: D
authors.lastname: Tremblay
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D048289:Imidazolidines; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011897:Random Allocation; D051381:Rats; D012016:Reference Values
chemical_list: D000726:Androgen Antagonists; D007093:Imidazoles; D048289:Imidazolidines; C021277:nilutamide