Oncotarget

Clinical Research Papers:

Combined use of irinotecan with histone deacetylase inhibitor belinostat could cause severe toxicity by inhibiting SN-38 glucuronidation via UGT1A1

Lingzhi Wang, Chong En Linus Chan, Andrea Li-Ann Wong, Fang Cheng Wong, Siew Woon Lim, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Lawrence Soon-U Lee, Ross Soo, Wei Peng Yong, Soo Chin Lee, Paul Chi-Lui Ho, Gautam Sethi and Boon Cher Goh _

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Oncotarget. 2017; 8:41572-41581. https://doi.org/10.18632/oncotarget.15017

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Abstract

Lingzhi Wang1,2,*, Chong En Linus Chan1,3,*, Andrea Li-Ann Wong1,4, Fang Cheng Wong1, Siew Woon Lim3,4, Arunachalam Chinnathambi5, Sulaiman Ali Alharbi5, Lawrence Soon-U Lee2, Ross Soo1,4, Wei Peng Yong1,4, Soo Chin Lee1,4, Paul Chi-Lui Ho3, Gautam Sethi2,5,6 and Boon Cher Goh1,2,4

1 Cancer Science Institute of Singapore, National University of Singapore, Singapore

2 Department of Pharmacology, National University Health System, Singapore

3 Department of Pharmacy, National University of Singapore, Singapore

4 Department of Haematology-Oncology, National University Health System, Singapore

5 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia

6 School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth WA, Australia

* These authors have contributed equally to this work

Correspondence to:

Boon Cher Goh, email:

Gautam Sethi, email:

Keywords: drug-drug interactions; irinotecan; SN-38; belinostat; UGT1A1

Received: September 07, 2016 Accepted: January 07, 2017 Published: February 02, 2017

Abstract

SN-38, the active metabolite of irinotecan, and histone deacetylase inhibitors (HDACis) such as belinostat, vorinostat and panobinostat, have all been shown to be deactivated by glucuronidation via UGTs. Since they all compete for UGTs for deactivation, we aimed to investigate the inhibitory effect of various HDACis on the glucuronidation of SN-38. This inhibitory effect was determined by measuring the formation rate of SN-38 glucuronide after SN-38 incubation with human recombinant UGT1A isoforms (1A1, 1A6, 1A7 and 1A9) and pooled human liver microsomes (HLM, wild type, UGT1A1*1*28 and UGT1A1*28*28 allelic variants), with and without HDACis. The data showed that belinostat at 100 and 200 µmol/L inhibited SN-38 glucuronidation via UGT1A1 in a dose-dependent manner, causing significant decrease in Vmax and CLint (p < 0.05) from 12.60 to 1.95 pmol/min/mg and 21.59 to 4.20 μL/min/mg protein respectively. Similarly, in HLMs, Vmax dropped from 41.13 to 10.54, 24.96 to 3.77 and 6.23 to 3.30 pmol/min/mg, and CLint reduced from 81.25 to 26.11, 29.22 to 6.10 and 5.40 to 1.34 µL/min/mg protein for the respective wild type, heterozygous and homozygous variants. Interestingly, belinostat at 200 µmol/L that is roughly equivalent to the average Cmax, 183 µmol/L of belinostat at a dose of 1,400 mg/m2 given intravenously once per day on days 1 to 5 every 3 weeks, was able to inhibit both heterozygous and homozygous variants to same extents (~64%). This highlights the potential clinical significance, as a large proportion of patients could be at risk of developing severe toxicity if irinotecan is co-administered with belinostat.


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