title: Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: Implications for hyperbilirubinemia.
abstract: Kinase inhibitors (KIs) are a rapidly expanding class of drugs used primarily for the treatment of cancer. Data relating to the inhibition of UDP-glucuronosyltransferase (UGT) enzymes by KIs is sparse. However, lapatinib (LAP), pazopanib (PAZ), regorafenib (REG) and sorafenib (SOR) have been implicated in the development of hyperbilirubinemia in patients. This study aimed to characterise the role of UGT1A1 inhibition in hyperbilirubinemia and assess the broader potential of these drugs to perpetrate drug-drug interactions arising from UGT enzyme inhibition. Twelve recombinant human UGTs from subfamilies 1A and 2B were screened for inhibition by LAP, PAZ, REG and SOR. IC50values for the inhibition of all UGT1A enzymes, except UGT1A3 and UGT1A4, by the four KIs were <10μM. LAP, PAZ, REG and SOR inhibited UGT1A1-catalysed bilirubin glucuronidation with mean IC50values ranging from 34nM (REG) to 3734nM (PAZ). Subsequent kinetic experiments confirmed that REG and SOR were very potent inhibitors of human liver microsomal β-estradiol glucuronidation, an established surrogate for bilirubin glucuronidation, with mean Kivalues of 20 and 33nM, respectively. Kivalues for LAP and PAZ were approximately 1- and 2-orders of magnitude higher than those for REG and SOR. REG and SOR were equipotent inhibitors of human liver microsomal UGT1A9 (mean Ki678nM). REG and SOR are the most potent inhibitors of a human UGT enzyme identified to date. In vitro-in vivo extrapolation indicates that inhibition of UGT1A1 contributes significantly to the hyperbilirubinemia observed in patients treated with REG and SOR, but not with LAP and PAZ. Inhibition of other UGT1A1 substrates in vivo is likely.
authors.affiliation: Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide, Australia; Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Adelaide, Australia. Electronic address: John.miners@flinders.edu.au.
authors.forename: John O
authors.initials: JO
authors.lastname: Miners
authors.affiliation: Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide, Australia. Electronic address: Nuy.chau@flinders.edu.au.
authors.forename: Nuy
authors.initials: N
authors.lastname: Chau
authors.affiliation: Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide, Australia; Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Adelaide, Australia. Electronic address: Andrew.rowland@flinders.edu.au.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowland
authors.affiliation: Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide, Australia. Electronic address: Kushari.burns@unisa.edu.au.
authors.forename: Kushari
authors.initials: K
authors.lastname: Burns
authors.affiliation: Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Adelaide, Australia. Electronic address: Ross.mckinnon@flinders.edu.au.
authors.forename: Ross A
authors.initials: RA
authors.lastname: McKinnon
authors.affiliation: Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide, Australia; Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Adelaide, Australia. Electronic address: Peter.mackenzie@flinders.edu.au.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Mackenzie
authors.affiliation: Department of Human Metabolism, Medical and Biological Sciences (Emeritus), University of Sheffield, Sheffield, United Kingdom. Electronic address: G.t.tucker@sheffield.ac.uk.
authors.forename: Geoffrey T
authors.initials: GT
authors.lastname: Tucker
authors.affiliation: Department of Clinical Pharmacology, Flinders University School of Medicine, Adelaide, Australia. Electronic address: Kathie.knights@flinders.edu.au.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Knights
authors.affiliation: Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Adelaide, Australia; Department of Oncology, Flinders Medical Centre, Bedford Park, Australia. Electronic address: Ganessan.kichenadasse@health.sa.gov.au.
authors.forename: Ganessan
authors.initials: G
authors.lastname: Kichenadasse
mesh_terms: D001663:Bilirubin / Q000378:metabolism; D002384:Catalysis; D004791:Enzyme Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced*; D007191:Indazoles; D007700:Kinetics; D000077341:Lapatinib; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000009:adverse effects* / Q000494:pharmacology; D011725:Pyridines / Q000009:adverse effects* / Q000494:pharmacology; D011743:Pyrimidines / Q000009:adverse effects* / Q000494:pharmacology; D011799:Quinazolines / Q000009:adverse effects* / Q000494:pharmacology; D000077157:Sorafenib; D013449:Sulfonamides / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D010671:Phenylurea Compounds; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D013449:Sulfonamides; D000077341:Lapatinib; C559147:regorafenib; D009536:Niacinamide; C516667:pazopanib; D000077157:Sorafenib; D014453:Glucuronosyltransferase; D001663:Bilirubin
keywords: Bilirubin (PubChem CID: 5280352); Drug–drug interaction; Drug–endobiotic interaction; Enzyme inhibition; Hyperbilirubinemia; Kinase inhibitors; Lapatinib (PubChem CID: 208908); Pazopanib (PubChem CID: 10113978); Propofol (PubChem CID: 4943); Regorafenib (PubChem CID: 178102514); Sorafenib (PubChem CID: 216239); UDP-glucuronosyltransferase; β-Estradiol (PubChem CID: 5757)