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VegfPharmacokinetic characterization of 14C-vascular endothelial growth factor controlled release microspheres using a rat model The objectives of this study were to characterize the pharmacokinetics of vascular endothelial growth factor (VEGF) in poly(lactic-co-glycolic) (PLGA) acid microspheres using a rat model, and to develop a pharmacokinetic model for this controlled release formulation. 14C-VEGF was encapsulated using a solid-in-oil-in-water emulsification method. The microspheres were administered subcutaneously to rats and the pharmacokinetic parameters were compared with those of protein solutions. Intravenous administration of protein solutions resulted in short half-lives and subcutaneous administration resulted in rapid clearance from the subcutaneous tissue, with high plasma concentrations as expressed by rapid absorption and elimination. The subcutaneous administration of the VEGF microspheres produced low plasma concentrations and high subcutaneous concentrations over a period of 7 weeks. The area under the curve (AUC), the time required to achieve the maximum concentration (tmax), and the maximum concentration (Cmax) in blood samples and the elimination rate constant (kel) values at the subcutaneous tissue site were selected to compare the pharmacokinetic characterization of VEGF microspheres with that of protein solutions. The in-vivo release profiles of the proteins were slower than the in-vitro release profiles and they followed the same trend as the in-vitro and in-vivo PLGA degradation rates. The PLGA microsphere degradation was the determinant step for VEGF release from the microspheres and its absorption at the subcutaneous site. Microspheres appear to be an attractive system for the localized rate-controlled delivery of VEGF. 14C-Methylation via reductive alkylation of VEGF did not affect its mitogenic activity, however, approximately 25%activity was lost following release from PLGA microspheres. This loss of activity may be owing to degradation in an acidic environment as a result of PLGA degradation. The administration of protein solutions via intravenous or subcutaneous injection may not be effective as a result of their rapid clearance rates.PLGAmicrospheres are a promising strategy for the controlled delivery of therapeutic proteins. Release of VEGF from the PLGA microspheres was measured using 14C-methylation of VEGF. 14C-Methylation did not affect the mitogenic activity of VEGF. However, the activity of VEGF was reduced by 25% following release from the PLGA microspheres. This was considered to be a result of acid degradation as a consequence of the acid environment created in the microspheres following PLGA degradation. The release profile of VEGF was different in the in-vitro and in-vivo environments. Therefore, the in vitro release kinetics of VEGF from the controlledrelease PLGA microsphere system could not be directly applied to predict the in-vivo absorption rate owing to complex biological responses to the PLGA and the released proteins. However, in-vitro and in-vivo release did follow the same rank order as the in-vitro and invivo degradation of the PLGA microspheres. In order to model the pharmacokinetic profile of VEGF from microspheres injected at the subcutaneous site, the conventional one-compartment open model was modified. An additional parameter, R, was included to describe the sustained release profile, where R is the concentration of protein in the tissue that has been already released from the microspheres. The protein absorption at the subcutaneous site included both the release rate from microspheres, which was the dominant step, and the absorption rate at the subcutaneous site. Finally, we propose that four pharmacokinetic parameters (AUC, tmax, Cmax in blood and kel at the subcutaneous site) were useful to characterize this sustained release dosage form and to compare the data with those from protein solution. By Tae-Kyoung Kim and Diane J. Burgess
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