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Vorinostat with Sustained Exposure and High Solubility in Poly(ethylene glycol)-b-poly(DL-lactic acid) Micelle Nanocarriers: Characterization and Effects on Pharmacokinetics in Rat Serum and Urine
Mohamed, Elham A. ; Zhao, Yunqi ; Meshali, Mahasen M. ; Remsberg, Connie M. ; Borg, Thanaa M. ; Foda, Abdel Monem M. ; Takemoto, Jody K. ; Sayre, Casey ; Martinez, Stephanie A. ; Davies, Neal M. ... show 1 more
Mohamed, Elham A.
Zhao, Yunqi
Meshali, Mahasen M.
Remsberg, Connie M.
Borg, Thanaa M.
Foda, Abdel Monem M.
Takemoto, Jody K.
Sayre, Casey
Martinez, Stephanie A.
Davies, Neal M.
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Abstract
The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anti-cancer drug with a unique mode of action; however, it is plagued by low water solubility, low permeability, and suboptimal pharmacokinetics. In this study, poly(ethylene glycol)-b-poly(DL-lactic acid) (PEG-b-PLA) micelles of vorinostat were developed. Vorinostat’s pharmacokinetics in rats were investigated after intravenous (i.v.) (10 mg/kg) and oral (50 mg/kg) micellar administrations and compared to a conventional PEG400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 mg/ml to 8.15 ± 0.60 mg/ml and 10.24 ± 0.92 mg/ml at drug to nanocarrier ratios of 1:10 and 1:15, respectively. Micelles had nanoscopic mean diameters of 75.67 ± 7.57 nm and 87.33 ± 8.62 nm for 1:10 and 1:15 micelles, respectively, with drug loading capacities of 9.93 ± 0.21% and 6.91 ± 1.19 %, and encapsulation efficiencies of 42.74 ± 1.67% and 73.29 ± 4.78%, respectively. The micelles provided sustained exposure and improved pharmacokinetics characterized by a significant increase in serum half-life, area under curve, and mean residence time. The micelles reduced vorinostat clearance particularly after i.v. dosing. Thus, PEG-b-PLA micelles significantly improved the oral and intravenous pharmacokinetics and bioavailability of vorinostat, which warrants further investigation.
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Date
2012-10
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Publisher
Elsevier
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Keywords
Nanocarrier, Pharmacokinetics, Polymeric micelles, PEG-b-PLA
Citation
Mohamed, E. A., Zhao, Y., Meshali, M. M., Remsberg, C. M., Borg, T. M., Foda, A. M. M., … Forrest, M. L. (2012). Vorinostat with Sustained Exposure and High Solubility in Poly(ethylene glycol)-b-poly(DL-lactic acid) Micelle Nanocarriers: Characterization and Effects on Pharmacokinetics in Rat Serum and Urine. Journal of Pharmaceutical Sciences, 101(10), 3787–3798. http://doi.org/10.1002/jps.23265