A Cashen

A Tumber

AL Yoder Graber

Andrea Li-Ann Wong

Anthony Chan

Boon-Cher Goh

BS Mann

C Marco

CP Strassburg

CS Mitsiades

E Beutler

F Innocenti

G Giaccone

HJ Mackay

How-Sung Lee

Jacqueline Ramírez

Jie-Ying Amelia Lau

JM Hoskins

John Luk

L Iyer

LH Du

Ling-Zhi Wang

LZ Wang

Mark J. Ratain

Mei-Yi Michelle Chan

MJ Peart

N Tanji

NL Steele

NS Wong

PA Marks

Paul C. Ho

PJ Bosma

RA Howman

RL Piekarz

RM Balliet

Robert Lim

S Clive

SA Bapat

Seow-Ching Wan

SG Gray

Sherry Ansher

Soo-Chin Lee

SP Kang

SR Babu

SS Ramalingam

T Izukawa

T Shiraga

W Yeo

Win-Lwin Thuya

Winnie Yeo

Y Dai

Ying-Kiat Zee

YS Na

PLoS ONE

PubMed

<div><p>Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-cell lymphoma and is undergoing clinical trials for non-hematologic malignancies. We studied the pharmacokinetics of belinostat in hepatocellular carcinoma patients to determine the main pathway of metabolism of belinostat. The pharmacokinetics of belinostat in liver cancer patients were characterized by rapid plasma clearance of belinostat with extensive metabolism with more than 4-fold greater relative systemic exposure of major metabolite, belinostat glucuronide than that of belinostat. There was significant interindividual variability of belinostat glucuronidation. The major pathway of metabolism involves UGT1A1-mediated glucuronidation and a good correlation has been identified between belinostat glucuronide formation and glucuronidation of known UGT1A1 substrates. In addition, liver microsomes harboring UGT1A1*28 alleles have lower glucuronidation activity for belinostat compared to those with wildtype UGT1A1. The main metabolic pathway of belinostat is through glucuronidation mediated primarily by UGT1A1, a highly polymorphic enzyme. The clinical significance of this finding remains to be determined.</p> <h3>Trial Registration</h3><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT00321594">NCT00321594</a></p> </div

Ling-Zhi Wang (277888)

Jacqueline Ramírez (5651281)

Winnie Yeo (197426)

Mei-Yi Michelle Chan (277889)

Win-Lwin Thuya (277890)

Jie-Ying Amelia Lau (277891)

Seow-Ching Wan (277892)

Andrea Li-Ann Wong (277893)

Ying-Kiat Zee (277894)

Robert Lim (277895)

Soo-Chin Lee (132913)

Paul C. Ho (277896)

How-Sung Lee (277897)

Anthony Chan (277898)

Sherry Ansher (277899)

Mark J. Ratain (25629)

Boon-Cher Goh (142783)

The Francis Crick Institute

Glucuronidation by UGT1A1 Is the Dominant Pathway of the Metabolic Disposition of Belinostat in Liver Cancer Patients

Wang Ling-Zhi

Ramírez Jacqueline

Yeo Winnie

Chan Mei-Yi Michelle

Thuya Win-Lwin

Lau Jie-Ying Amelia

Wan Seow-Ching

Wong Andrea Li-Ann

Zee Ying-Kiat

Lim Robert

Lee Soo-Chin

Ho Paul C.

Lee How-Sung

Chan Anthony

Ansher Sherry

Ratain Mark J.

Goh Boon-Cher

Public Library of Science (PLOS)

Crossref

Belinostat is a hydroxamate class HDAC inhibitor that has demonstrated activity in peripheral T-cell lymphoma and is undergoing clinical trials for non-hematologic malignancies. We studied the pharmacokinetics of belinostat in hepatocellular carcinoma patients to determine the main pathway of metabolism of belinostat. The pharmacokinetics of belinostat in liver cancer patients were characterized by rapid plasma clearance of belinostat with extensive metabolism with more than 4-fold greater relative systemic exposure of major metabolite, belinostat glucuronide than that of belinostat. There was significant interindividual variability of belinostat glucuronidation. The major pathway of metabolism involves UGT1A1-mediated glucuronidation and a good correlation has been identified between belinostat glucuronide formation and glucuronidation of known UGT1A1 substrates. In addition, liver microsomes harboring UGT1A1*28 alleles have lower glucuronidation activity for belinostat compared to those with wildtype UGT1A1. The main metabolic pathway of belinostat is through glucuronidation mediated primarily by UGT1A1, a highly polymorphic enzyme. The clinical significance of this finding remains to be determined.ClinicalTrials.gov NCT00321594

Paul C Ho

Mark J Ratain

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The Francis Crick Institute

Public Library of Science (PLOS)

Crossref

Directory of Open Access Journals