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

Youssef W Naguib; Brittany E Givens; Giang Ho; Yang Yu; Shun-Guang Wei; Robert M Weiss; Robert B Felder; Aliasger K Salem

doi:10.1007/s13346-020-00758-9

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

Journal article

Peer reviewed

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

Youssef W Naguib, Brittany E Givens, Giang Ho, Yang Yu, Shun-Guang Wei, Robert M Weiss, Robert B Felder and Aliasger K Salem

Drug delivery and translational research, Vol.11(1), pp.182-191

02/2021

DOI: 10.1007/s13346-020-00758-9

PMCID: PMC7647946

PMID: 32378175

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https://www.ncbi.nlm.nih.gov/pmc/articles/7647946View

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Abstract

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.

Heart failure

LC/MS

PD98059

Sustained release

MEK1/2 inhibitor

Microparticles

Details

Title: Subtitle: An injectable microparticle formulation for the sustained release of the specific MEK inhibitor PD98059: in vitro evaluation and pharmacokinetics
Creators: Youssef W Naguib - Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt
Brittany E Givens - Department of Chemical and Materials Engineering, University of Kentucky, Lexington, KY, 40506, USA
Giang Ho - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, 52242, USA
Yang Yu - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Shun-Guang Wei - Francois M. Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Robert M Weiss - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Robert B Felder - Francois M. Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA
Aliasger K Salem - Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA. aliasger-salem@uiowa.edu
Resource Type: Journal article
Publication Details: Drug delivery and translational research, Vol.11(1), pp.182-191
DOI: 10.1007/s13346-020-00758-9
PMID: 32378175
PMCID: PMC7647946
NLM abbreviation: Drug Deliv Transl Res
ISSN: 2190-393X
eISSN: 2190-3948
Publisher: United States
Grant note: S10 OD019941 / NIH HHS P30 ES005605 / NIEHS NIH HHS S10-OD-019941 / NIH HHS P30 CA086862 / NCI NIH HHS R01-HL-136149 / NIH HHS R01 HL136149 / NHLBI NIH HHS
Language: English
Date published: 02/2021
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Cardiovascular Medicine; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering; Internal Medicine
Record Identifier: 9984070812002771

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