title: Effect of glucuronidation on transport and tissue accumulation of tyrosine kinase inhibitors: consequences for the clinical management of sorafenib and regorafenib.
abstract: BACKGROUND
  UDP-glucuronosyltransferases (UGTs) are a multigenic family of enzymes responsible for the glucuronidation reaction. Many therapeutic classes of drugs used in solid tumors are UGT substrates, including cancer therapies.
  
  
  METHODS
  This article describes the tyrosine kinase inhibitors (TKIs) undergoing hepatic glucuronidation; its effect on transport and tissue accumulation and the clinical consequences of this particular metabolism. A PubMed search concerning the pharmacokinetics of the TKIs was performed. All are extensively metabolized by CYP450. Two TKIs, sorafenib and regorafenib, also have a major UGT-mediated metabolism and were therefore studied.
  
  
  CONCLUSIONS
  The prescription of the same dose of sorafenib and regorafenib for all patients may be inappropriate since at each enzymatic step of this multistep metabolism inter-individual fluctuations exist. Having a non-exclusive CYP-mediated route of metabolism may reduce the risk of variability in drug exposure when CYP3A4 substrates are concomitantly given. Several clinical consequences derive from this pharmacokinetic particularity of sorafenib and regorafenib. Since no clear difference distinguishes TKIs in efficacy in large randomized trials, the differences for the clinical management of their toxicity is a critical aspect.
authors: Paris Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA) , Paris , France 33 1 58 41 17 46 ; 33 1 58 41 17 45 ; camille.tlemsani@cch.aphp.fr.
authors: Camille
authors: C
authors: Tlemsani
authors: Olivier
authors: O
authors: Huillard
authors: Jennifer
authors: J
authors: Arrondeau
authors: Pascaline
authors: P
authors: Boudou-Rouquette
authors: Anatole
authors: A
authors: Cessot
authors: Benoit
authors: B
authors: Blanchet
authors: Audrey
authors: A
authors: Thomas-Schoemann
authors: Romain
authors: R
authors: Coriat
authors: Jean-Philippe
authors: JP
authors: Durand
authors: Julie
authors: J
authors: Giroux
authors: Jérôme
authors: J
authors: Alexandre
authors: François
authors: F
authors: Goldwasser
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001692:Biological Transport; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics; D016032:Randomized Controlled Trials as Topic; D000077157:Sorafenib; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D020719:Glucuronides; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib; D009536:Niacinamide; D000077157:Sorafenib; D014453:Glucuronosyltransferase
keywords: CYP450; UDP-glucuronosyltransferases; glucuronidation; regorafenib; sorafenib; tyrosine kinase inhibitors