title: Metabolism, Excretion and Pharmacokinetics of MLN3897, a CCR1 Antagonist, in Humans.
abstract: MLN3897 is a small molecule antagonist of the C-C chemokine receptor-1. Since preclinical studies showed that the molecule was metabolized into two halves, the metabolism, excretion, and pharmacokinetics of MLN3897 were investigated in humans using MLN3897 14C-radiolabeled either on the chlorophenyl (CP) or the tricyclic (TC) half of MLN3897 after an oral dose.
  
  
  OBJECTIVE
  To evaluate the mass balance, metabolism and pharmacokinetics of MLN3897 in two cohorts of six randomized healthy subjects.
  
  
  METHODS
  After receiving informed consent, subjects were dosed after an overnight fast of 10-hours followed by at least 4- hours after dosing on day-1. Each cohort received a single 29 mg oral dose of either the CP or the TC as an oral solution in water. Serial blood samples, urine and feces were collected over a 10-day period post-dose.
  
  
  RESULTS
  For both radiolabeled moieties, 55-59% of the dose was recovered in feces and 32% recovered in urine. MLN3897 was metabolized extensively in humans, with minor amounts of intact MLN3897 detected in the urine and feces. N-oxidation of the tricyclic moiety (M28) and N-dealkylation of the piperidinyl moiety were the primary metabolic pathways leading to further formation of the carboxylic acid metabolite (M19) and the (4-(4-chlorophenyl)-3,3- dimethylpiperidin-4-ol) metabolite (M40). Oxidative metabolites M11, M19, M28, M44 were present at >10% of the total circulating radioactivity and also at >25% of MLN3897 exposure. Metabolites resulting from the chlorophenyl-labeled moiety (M40) had significantly more systemic exposure compared to the tricyclic-labeled moiety (M19).
authors.affiliation: Department of Metabolism and Pharmacokinetics, Takeda Pharmaceuticals Inc. Cambridge, MA 02139.. Sandeepraj.Pusalkar@takeda.com.
authors.forename: Sandeepraj
authors.initials: S
authors.lastname: Pusalkar
authors.forename: Mihaela
authors.initials: M
authors.lastname: Plesescu
authors.forename: Mark
authors.initials: M
authors.lastname: Milton
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Balani
authors.forename: Swapan
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Shimoga
authors.initials: S
authors.lastname: Prakash
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001584:Benzoxepins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D001711:Biotransformation; D002264:Carboxylic Acids / Q000378:metabolism; D003640:Dealkylation; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D066237:Intestinal Elimination; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010084:Oxidation-Reduction; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D017207:Rats, Sprague-Dawley; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D065667:Renal Elimination
chemical_list: D000893:Anti-Inflammatory Agents; D001584:Benzoxepins; C515300:CCR1 protein, human; D002264:Carboxylic Acids; C000612649:MLN3897; D011725:Pyridines; D054389:Receptors, CCR1