An injectable microparticle formulation for the sustained release of the specific MEK inhibitor PD98059: in vitro evaluation and pharmacokinetics

Drug Deliv Transl Res. 2021 Feb;11(1):182-191. doi: 10.1007/s13346-020-00758-9.


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.

Keywords: Heart failure; LC/MS; MEK1/2 inhibitor; Microparticles; PD98059; Sustained release.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Delayed-Action Preparations
  • Flavonoids*
  • Microspheres
  • Mitogen-Activated Protein Kinase Kinases*
  • Particle Size
  • Rats
  • Tissue Distribution


  • Delayed-Action Preparations
  • Flavonoids
  • Mitogen-Activated Protein Kinase Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one