EZH2 Inhibitor GSK126: Metabolism, drug transporter and rat pharmacokinetic studies

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Amit Kumar Vijay Kumar Janet Lightner Anaheed Little Promsuk Jutabha Hitoshi Endou Peter Rice Philip Reigan Rajeev Vibhakar Peter Harris Ilango Balakrishnan Ilango Sujatha Venkataraman Marielle Nebout Jean-Francois Peyron Michael F. Wempe


Histone lysine methyl transferase 2 (EZH2) inhibitor GSK126 and a novel deuterated internal standard GSK126-d7 were chemically prepared. We performed in vitro experiments using the prepared GSK126 to: i) confirm in vitro EZH2 inhibitory activity; ii) conduct Sprague-Dawley (SD) rat liver microsomal incubations and identified Phase I metabolites; iii) determine whether or not GSK126 was an Organic Anion Transporter (OAT) substrate; and, iv) determine oral bioavailability by conducting oral and orbital sinus dosing (OSD) experiments and determining blood concentration versus time profiles. GSK126 was shown to decrease the expression of H3K27Me3 protein in medulloblastoma D283 cells and was able to decrease cell viability in KO99L cells, a novel T cell lymphoma cell line. Three in vitro hepatic Phase I mono-oxidative metabolites (L-M1, L-M2 and L-M3) were observed and also detected in rat liver and urine samples from the in vivo studies.  GSK126 was found to be an OAT1 and OAT2 substrate, but not an OAT3 or OAT4 substrate. Our Pharmacokinetic (PK) results indicate: 1) GSK126 has very poor oral bioavailability (< 2%); 2) co-administration of probenecid, a prototypical OAT inhibitor, did not significantly alter observed PK; and 3) tissue distribution studies demonstrate that GSK126 predominately distributes to the liver and kidneys after an OSD.

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KUMAR, Amit et al. EZH2 Inhibitor GSK126: Metabolism, drug transporter and rat pharmacokinetic studies. Medical Research Archives, [S.l.], n. 3, june 2015. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/273>. Date accessed: 19 july 2024.
EZH2 Inhibitor; GSK126 and GSK126-d7; OAT’s; Drug Metabolism; Rat Pharmacokinetic Study
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