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Largazole Pharmacokinetics in Rats by LC-MS/MS

Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL 32610, USA
Department of Chemistry, Duke University, Durham, NC 27708, USA
Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
Marine Science Institute, College of Science, University of the Philippines, Diliman, Quezon City, 1100, Philippines
Author to whom correspondence should be addressed.
Mar. Drugs 2014, 12(3), 1623-1640;
Received: 14 October 2013 / Revised: 30 January 2014 / Accepted: 27 February 2014 / Published: 20 March 2014
A highly sensitive and specific LC-MS/MS method for the quantitation of largazole thiol, the active species of the marine-derived preclinical histone deacetylase inhibitor, largazole (prodrug), was developed and validated. Largazole thiol was extracted with ethyl acetate from human or rat plasma along with the internal standard, harmine. Samples were separated on an Onyx Monolithic C18 column by a stepwise gradient elution with 0.1% formic acid in methanol and 0.1% aqueous formic acid employing multiple reaction monitoring (MRM) detection. Linear calibration curves were obtained in the range of 12.5–400 ng/mL with 200 µL of human plasma. The overall intra-day precision was from 3.87% to 12.6%, and the inter-day precision was from 7.12% to 9.8%. The accuracy at low, medium and high concentrations ranged from 101.55% to 105.84%. Plasma protein bindings of largazole thiol in human and rat plasma as determined by an ultrafiltration method were 90.13% and 77.14%, respectively. Plasma drug concentrations were measured by this LC-MS/MS method. The pharmacokinetics of largazole thiol in rats was studied following i.v. administration at 10 mg/kg and found to follow a two-compartment model. Largazole thiol was rapidly eliminated from systemic circulation within 2 h. The established LC-MS/MS method is suitable for the analysis of largazole thiol in human plasma, as well. View Full-Text
Keywords: largazole; LC-MS/MS; pharmacokinetics; protein binding largazole; LC-MS/MS; pharmacokinetics; protein binding
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Yu, M.; Salvador, L.A.; Sy, S.K.B.; Tang, Y.; Singh, R.S.P.; Chen, Q.-Y.; Liu, Y.; Hong, J.; Derendorf, H.; Luesch, H. Largazole Pharmacokinetics in Rats by LC-MS/MS. Mar. Drugs 2014, 12, 1623-1640.

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