An injectable microparticle formulation for the sustained release of the specific MEK inhibitor PD98059: in vitro evaluation and pharmacokinetics.
PD98059 is a reversible MEK inhibitor that we are investigating as a potential treatment for neurochemical changes in the brain that drive neurohumoral excitation in heart failure. In a rat model that closely resembles human heart failure, we found that central administration of PD98059 inhibits phosphorylation of ERK1/2 in the paraventricular nucleus of the hypothalamus, ultimately reducing sympathetic excitation which is a major contributor to clinical deterioration. Studies revealed that the pharmacokinetics and biodistribution of PD98059 match a two-compartment model, with drug found in brain as well as other body tissues, but with a short elimination half-life in plasma (approximately 73 min) that would severely limit its potential clinical usefulness in heart failure. To increase its availability to tissues, we prepared a sustained release PD98059-loaded PLGA microparticle formulation, using an emulsion solvent evaporation technique. The average particle size, yield percent, and encapsulation percent were found to be 16.73 μm, 76.6%, and 43%, respectively. In vitro drug release occurred over 4 weeks, with no noticeable burst release. Following subcutaneous injection of the microparticles in rats, steady plasma levels of PD98059 were detected by HPLC for up to 2 weeks. Furthermore, plasma and brain levels of PD98059 in rats with heart failure were detectable by LC/MS, despite expected erratic absorption. These findings suggest that PD98059-loaded microparticles hold promise as a novel therapeutic intervention countering sympathetic excitation in heart failure, and perhaps in other disease processes, including cancers, in which activated MAPK signaling is a significant contributing factor. Graphical abstract.
['Naguib|Youssef W|YW|0000-0002-3686-8392', 'Givens|Brittany E|BE|0000-0002-6386-7766', 'Ho|Giang|G|', 'Yu|Yang|Y|', 'Wei|Shun-Guang|SG|', 'Weiss|Robert M|RM|', 'Felder|Robert B|RB|', 'Salem|Aliasger K|AK|']
D000818:Animals D003692:Delayed-Action Preparations D005419:Flavonoids D008863:Microspheres D020929:Mitogen-Activated Protein Kinase Kinases D010316:Particle Size D051381:Rats D014018:Tissue Distribution
Microparticles Sustained release PD98059 Heart failure LC/MS MEK1/2 inhibitor