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.
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.
College of Pharmacy, Department of Pharmaceutical Sciences, Washington State University, Pullman, Washington 99164-6534, USA.
Elham A
EA
Mohamed
Yunqi
Y
Zhao
Mahasen M
MM
Meshali
Connie M
CM
Remsberg
Thanaa M
TM
Borg
Abdel Monem M
AM
Foda
Jody K
JK
Takemoto
Casey L
CL
Sayre
Stephanie E
SE
Martinez
Neal M
NM
Davies
M Laird
ML
Forrest
D000818:Animals; D001682:Biological Availability; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D006207:Half-Life; D006877:Hydroxamic Acids / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000652:urine; D007773:Lactates / Q000008:administration & dosage / Q000737:chemistry*; D008297:Male; D008747:Methylcellulose / Q000008:administration & dosage / Q000737:chemistry; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013535:Suspensions / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000077337:Vorinostat
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006877:Hydroxamic Acids; D007773:Lactates; D008823:Micelles; D013535:Suspensions; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; D000077337:Vorinostat; D008747:Methylcellulose