title: Metabolism and disposition of a potent and selective JNK inhibitor [14C]tanzisertib following oral administration to rats, dogs and humans.
abstract: 1. The disposition of tanzisertib [(1S,4R)-4-(9-((S)tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino) cyclohexanol], a potent, orally active c-Jun amino-terminal kinase inhibitor intended for treatment of fibrotic diseases was studied in rats, dogs and humans following a single oral dose of [(14)C]tanzisertib (Independent Investigational Review Board Inc., Plantation, FL). 2. Administered dose was quantitatively recovered in all species and feces/bile was the major route of elimination. Tanzisertib was rapidly absorbed (Tmax: 1-2 h) across all species with unchanged tanzisertib representing >83% of plasma radioactivity in dogs and humans, whereas <34% was observed in rats. Variable amounts of unchanged tanzisertib (1.5-32% of dose) was recovered in urine/feces across all species, the highest in human feces. 3. Metabolic profiling revealed that tanzisertib was primarily metabolized via oxidation and conjugation pathways, but extensively metabolized in rats relative to dogs/humans. CC-418424 (S-cis isomer of tanzisertib) was the major plasma metabolite in rats (38.4-46.4% of plasma radioactivity), while the predominant plasma metabolite in humans and dogs was M18 (tanzisertib-/CC-418424 glucuronide), representing 7.7 and 3.2% of plasma radioactivity, respectively. Prevalent biliary metabolite in rats and dogs, M18 represented 16.8 and 17.1% of dose, respectively. 4. In vitro studies using liver subcellular fractions and expressed enzymes characterized involvement of novel human aldo-keto reductases for oxido-reduction and UDP-glucuronosyltransferases for conjugation pathways.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics and.
authors.forename: Christian
authors.initials: C
authors.lastname: Atsriku
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Ying
authors.initials: Y
authors.lastname: Ye
authors.forename: Gondi
authors.initials: G
authors.lastname: Kumar
authors.forename: Sekhar
authors.initials: S
authors.lastname: Surapaneni
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D003511:Cyclohexanols / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000008:administration & dosage*; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome; D055432:Metabolomics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D011687:Purines / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley
chemical_list: D002250:Carbon Radioisotopes; D003511:Cyclohexanols; D047428:Protein Kinase Inhibitors; D011687:Purines; D048031:JNK Mitogen-Activated Protein Kinases; C000606668:4-(9-(tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino)cyclohexanol
keywords: Bile duct-cannulated; C-Jun amino-terminal kinase; pharmacokinetics; renal fibrosis; tanzisertib