Received for publication February 27, 2007.
Revised March 29, 2007.
Accepted for publication April 10, 2007.

METABOLISM, PHARMACOKINETICS, AND EXCRETION OF A NONPEPTIDIC SUBSTANCE P RECEPTOR ANTAGONIST, EZLOPITANT, IN NORMAL HEALTHY MALE VOLUNTEERS

Abstract

The excretion, biotransformation and pharmacokinetics of ezlopitant, a substance P receptor antagonist, were investigated in healthy male volunteers after oral administration of a single 200 mg (~93 uCi/subject) dose of [¹⁴C]ezlopitant. The total recovery of administered radioactive dose was 82.8 ± 5.1, with 32.0 ± 4.2% in the urine and 50.8 ± 1.4% in the feces. Mean observed maximal serum concentrations for ezlopitant and total radioactivity were achieved at T2 h after oral administration, thus ezlopitant was rapidly absorbed. Ezlopitant was extensively metabolized in humans, since no unchanged drug was detected in urine and feces. The major pathway of ezlopitant in humans was due to the oxidation of the isopropyl side chain to form the -hydroxy and -1 hydroxy (M16) metabolites. M16 and , -1-dihydroxy (1, 2-dihydroxy, M12) were identified as the major circulating metabolites accounting for 64.6 and 15.4% of total circulating radioactivity, respectively. In feces, the major metabolite M14 was characterized as the propionic acid metabolite and formed by further oxidation of the w-hydroxy metabolite. The urinary metabolites were due to cleaved metabolites resulted by oxidative dealkylation of the 2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-yl moiety. The metabolites (M1A, M1B and M4), approximately 34% of the total radioactivity in urine, were identified as benzyl amine derivatives. These were polar metabolites that were further characterized using the reaction with dansyl chloride to derivatized the primary amines and phenol moieties to less polar analytes. The other metabolites were due to O-demethylation, dehydrogenation of the isopropyl group and oxidation on the quinuclidine moiety.

Key words: cytochrome P450 catalyzed oxidations, drug development, drug disposition, excretion, human pharmacokinetics, mass spectrometry, metabolite identification, pharmacokinetics