In vitro UGT1A1 inhibition by tyrosine kinase inhibitors and association with drug-induced hyperbilirubinemia
- 144 Downloads
Hyperbilirubinemia has been observed in patients treated with tyrosine kinase inhibitor (TKI) drugs. Therefore, it would be beneficial to understand whether there is a relationship between inhibition of uridine-5′-diphosphate glucuronosyltransferase (UGT) 1A1 activity and observed bilirubin elevations in TKI drug-treated patients. UGT1A1 is responsible for the glucuronidation of bilirubin which leads to its elimination in the bile.
To examine this question, an in vitro glucuronidation assay was developed to determine the inhibitory effect of TKI drugs employing human liver microsomes (HLM) with varying UGT1A1 activity. Utilizing β-estradiol as the UGT1A1 probe substrate, 20 TKI drugs were evaluated at concentrations that represent clinical plasma levels. Adverse event reports were searched to generate an empirical Bayes geometric mean (EGBM) score for clinical hyperbilirubinemia with the TKI drugs.
Erlotinib, nilotinib, regorafenib, pazopanib, sorafenib and vemurafenib had IC50 values that were lower than their clinical steady-state Cmax concentrations. These TKI drugs had high incidences of hyperbilirubinemia and higher EBGM scores. The IC50 values and Cmax/IC50 ratios correlated well with EBGM scores for hyperbilirubinemia (P < 0.005). For the TKI drugs with higher incidence of hyperbilirubinemia in Gilbert syndrome patients, who have reduced UGT1A1 activity, six of eight had smaller ratios in the low UGT1A1 activity microsomes than the wild-type microsomes for drugs, indicating greater sensitivity to the drugs in this phenotype.
These results suggest that in vitro UGT1A1 inhibition assays have the potential to predict clinical hyperbilirubinemia.
KeywordsTyrosine kinase inhibitors Hyperbilirubinemia UGT1A1 Polymorphisms
Drs. Qosa and Avaritt were supported by an appointment to the Research Participation Program at CDER, administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the US Department of Energy and the FDA. Special thanks to Dr. Peter Schotland for the Empirica Signal search.
The findings and conclusions in this article have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any agency endorsement, determination or policy.
Compliance with ethical standards
Conflict of interest
All the authors declare that they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
- 4.Daud A, Kluger HM, Edelman G, Gordon MS, Schimmoller F, Weitzman A, Samuel TS, Moussa AH, Flaherty K, Shapiro G (2013) Activity of cabozantinib in metastatic uveal melanoma: updated results from a phase II randomized discontinuation trial (RDT). J Clin Oncol 31(15_suppl):9094Google Scholar
- 5.Zhu AX, Ancukiewicz M, Supko JG, Sahani DV, Blaszkowsky LS, Meyerhardt JA, Abrams TA, McCleary NJ, Bhargava P, Muzikansky A, Sheehan S, Regan E, Vasudev E, Knowles M, Fuchs CS, Ryan DP, Jain RK, Duda DG (2013) Efficacy, safety, pharmacokinetics, and biomarkers of cediranib monotherapy in advanced hepatocellular carcinoma: a phase II study. Clin Cancer Res 19:1557–1566CrossRefGoogle Scholar
- 6.Miller AA, Murry DJ, Owzar K, Hollis DR, Lewis LD, Kindler HL, Marshall JL, Villalona-Calero MA, Edelman MJ, Hohl RJ, Lichtman SM, Ratain MJ (2007) Phase I and pharmacokinetic study of erlotinib for solid tumors in patients with hepatic or renal dysfunction: CALGB 60101. J Clin Oncol 25:3055–3060CrossRefGoogle Scholar
- 7.Ramanathan RK, Egorin MJ, Takimoto CH, Remick SC, Doroshow JH, LoRusso PA, Mulkerin DL, Grem JL, Hamilton A, Murgo AJ, Potter DM, Belani CP, Hayes MJ, Peng B, Ivy SP, National Cancer Institute Organ Dysfunction Working Group (2008) Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol 26:563–569CrossRefGoogle Scholar
- 8.Stebbing J, Payne R, Reise J, Frampton AE, Avery M, Woodley L, Di Leo A, Pestrin M, Krell J, Coombes RC (2013) The efficacy of lapatinib in metastatic breast cancer with HER2 non-amplified primary tumors and EGFR positive circulating tumor cells: a proof-of-concept study. PLoS ONE 8:e62543CrossRefGoogle Scholar
- 9.Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354:2542–2551CrossRefGoogle Scholar
- 11.Bruix J, Tak WY, Gasbarrini A, Santoro A, Colombo M, Lim HY, Mazzaferro V, Wiest R, Reig M, Wagner A, Bolondi L (2013) Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: Multicentre, open-label, phase II safety study. Eur J Cancer 49:3412–3419CrossRefGoogle Scholar
- 13.Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Maru D, Morris V, Janku F, Dasari A, Chung W, Issa J-PJ, Gibbs P, James B, Powis G, Nolop KB, Bhattacharya S, Saltz L (2015) Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J Clin Oncol 33:4032–4038CrossRefGoogle Scholar
- 17.Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG (2005) In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos 33:1729–1739CrossRefGoogle Scholar
- 18.Bahk J, Claudiani S, Szydlo RM, Toma S, Abdillah F, Hing S, Deplano S, Milojkovic D, Apperley JF, Foroni L (2015) The association of Gilbert’s syndrome with hyperbilirubinaemia occurring on any of imatinib, dasatinib and nilotinib in patients with chronic myeloid leukaemia (CML). Blood 126:2795Google Scholar
- 24.Wakatsuki T, Suenaga M, Shinozaki E, Nagayama S, Nakayama I, Matsushima T, Ogura M, Ichimura T, Takahari D, Chin K, Kumekawa Y, Sato Y, Fukunaga Y, Ueno M, Mizunuma N, Yamaguchi T (2015) Genetic variants of UGT1A1 and 1A9 could be associated with regorafenib induced toxicity in Japanese patients with metastatic colorectal cancer. Eur J Cancer 51(suppl. 3):S391CrossRefGoogle Scholar
- 30.Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236CrossRefGoogle Scholar
- 32.Zhang D, Zhang D, Cui D, Gambardella J, Ma L, Barros A, Wang L, Fu Y, Rahematpura S, Nielsen J, Donegan M, Zhang H, Humphreys WG (2007) Characterization of the UDP glucuronosyltransferase activity of human liver microsomes genotyped for the UGT1A1*28 polymorphism. Drug Metab Dispos 35:2270–2280CrossRefGoogle Scholar
- 40.Dohse M, Scharenberg C, Shukla S, Robey RW, Volkmann T, Deeken JF, Brendel C, Ambudkar SV, Neubauer A, Bates SE (2010) Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab Dispos 38:1371–1380CrossRefGoogle Scholar
- 42.Khurana V, Minocha M, Pal D, Mitra AK (2014) Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors. Drug Metab Drug Interact 29:249–259Google Scholar