Nanoparticles Containing Anti-inflammatory Agents as Chemotherapy Adjuvants II: Role of Plasma Esterases in Drug Release
Journal Title: The AAPS Journal - Year 2009, Vol 11, Issue 1
Abstract
The pre-administration of the anti-inflammatory drugs dexamethasone (DEX) and cortisone acetate reduces toxicity and enhances efficacy of anticancer agents in murine models and in human clinical trials (1–5). We previously reported on the formulation of the lipophilic dexamethasone palmitate ester (DEX-P) in nanoparticles (NPs) employing a microemulsion template engineering technique to achieve tumor-specific delivery of dexamethasone (6). The nanoparticles exhibited significantly enhanced stealth properties as indicated by reduced macrophage uptake and decreased adsorption of opsonin proteins in in vitro assays (6). Unexpectedly, preliminary biodistribution studies of NPs containing [3H]-DEX-P in tumor-bearing mice showed that the radiolabel was cleared from the circulation rapidly and exhibited high liver uptake. Our previous in vitro release studies demonstrated that rapid release of the radiolabel from the NPs was observed when 10% mouse plasma was used as the medium, while nominal release was observed in phosphate-buffered saline (PBS) buffer (6). Esterolysis of NP-associated DEX-P was presumed to be the main cause for the rapid drug release in plasma, as most of the released radioactivity was in the form of DEX and not DEX-P. High degradation rates of ester prodrugs in rodent plasma has been attributed to increased esterase activity, while only minimal degradation in human plasma has been observed (7–9). Based on our observation of the release of [3H]-DEX from NPs in mouse plasma, we studied the release of DEX from nanoparticles in various plasma sources as a guide for the design of future in vivo experiments.
Authors and Affiliations
Xiuling Lu, Melissa D. Howard, Dominique R. Talbert, John J. Rinehart, Philip M. Potter, Michael Jay, Markos Leggas
Keywords
Related Articles
- EP ID EP681454
- DOI 10.1208/s12248-009-9086-3
- Views 88
- Downloads 0
Modeling and simulation of adherence: Approaches and applications in therapeutics
Partial adherence with a prescribed or randomly assigned dose gives rise to unintended variability in actual drug exposure in clinical practice and during clinical trials. There are tremendous costs associated with incom...
An Extended Minimal Physiologically Based Pharmacokinetic Model: Evaluation of Type II Diabetes Mellitus and Diabetic Nephropathy on Human IgG Pharmacokinetics in Rats
Although many studies have evaluated the effects of type 2 diabetes mellitus (T2DM) on the pharmacokinetics (PK) of low molecular weight molecules, there is limited information regarding effects on monoclonal antibodies....
Use of Partial Area under the Curve Metrics to Assess Bioequivalence of Methylphenidate Multiphasic Modified Release Formulations
Neonatal Immune Tolerance Induction to Allow Long-Term Studies With an Immunogenic Therapeutic Monoclonal Antibody in Mice
The purpose of this study is to test the feasibility of neonatal immune tolerance induction in mice to enable long-term pharmacokinetic studies with immunogenic therapeutic monoclonal antibodies (mAb). Neonatal immune to...
An in vitro examination of the impact of polyethylene glycol 400, pluronic P85, and vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine