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
| Autor: | Neal M. Davies, Casey L. Sayre, Connie M. Remsberg, Jody K. Takemoto, Yunqi Zhao, Elham Abdelmonem Mohamed, Thanaa Mohamed Borg, Stephanie E. Martinez, M. Laird Forrest, M. M. Meshali, Abdel Monem M. Foda |
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| Rok vydání: | 2012 |
| Předmět: |
Male
medicine.drug_class Biological Availability Pharmaceutical Science Methylcellulose Hydroxamic Acids Micelle Article Polyethylene Glycols Rats Sprague-Dawley chemistry.chemical_compound Suspensions Pharmacokinetics medicine Animals Particle Size Solubility Vorinostat Micelles Drug Carriers Chromatography Chemistry Histone deacetylase inhibitor Rats Bioavailability Delayed-Action Preparations Lactates Nanoparticles Nanocarriers Ethylene glycol Half-Life medicine.drug |
| Zdroj: | Journal of Pharmaceutical Sciences. 101:3787-3798 |
| ISSN: | 0022-3549 |
| DOI: | 10.1002/jps.23265 |
| Popis: | The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anticancer 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 was investigated after intravenous (i.v.) (10 mg/kg) and oral (p.o.) (50 mg/kg) micellar administrations and compared with a conventional polyethylene glycol 400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 to 8.15 ± 0.60 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 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 p.o. and i.v. pharmacokinetics and bioavailability of vorinostat, which warrants further investigation. |
| Databáze: | OpenAIRE |
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