title: Decellularized skeletal muscle as an in vitro model for studying drug-extracellular matrix interactions.
abstract: Several factors can affect drug absorption after intramuscular (IM) injection: drug solubility, drug transport across cell membranes, and drug metabolism at the injection site. We found that potential interactions between the drug and the extracellular matrix (ECM) at the injection site can also affect the rate of absorption post-injection. Using decellularized skeletal muscle, we developed a simple method to model drug absorption after IM injection, and showed that the nature of the drug-ECM interaction could be investigated by adding compounds that alter binding. We validated the model using the vitamin B12 analog cobinamide with different bound ligands. Cobinamide is being developed as an IM injectable treatment for cyanide poisoning, and we found that the in vitro binding data correlated with previously published in vivo drug absorption in animals. Commercially available ECM products, such as collagen and GelTrex, did not recapitulate drug binding behavior. While decellularized ECM has been widely studied in fields such as tissue engineering, this work establishes a novel use of skeletal muscle ECM as a potential in vitro model to study drug-ECM interactions during drug development.
authors.affiliation: Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, USA.
authors.forename: Jean W
authors.initials: JW
authors.lastname: Wassenaar
authors.affiliation: Department of Medicine, University of California, San Diego, 92093, USA. Electronic address: gboss@ucsd.edu.
authors.forename: Gerry R
authors.initials: GR
authors.lastname: Boss
authors.affiliation: Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, USA. Electronic address: christman@eng.ucsd.edu.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Christman
mesh_terms: D000818:Animals; D003038:Cobamides / Q000008:administration & dosage; D003094:Collagen; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D020100:Hydrogels; D066298:In Vitro Techniques; D007273:Injections, Intramuscular; D065586:Intramuscular Absorption; D008024:Ligands; D018482:Muscle, Skeletal; D011134:Polysaccharides; D051381:Rats; D013431:Sulfates; D034421:Sus scrofa; D013552:Swine
chemical_list: D003038:Cobamides; D020100:Hydrogels; D008024:Ligands; D011134:Polysaccharides; D013431:Sulfates; C017142:cobinamide; D003094:Collagen
keywords: Absorption; Drug delivery; ECM; Muscle