title: Myocardial drug distribution generated from local epicardial application: potential impact of cardiac capillary perfusion in a swine model using epinephrine.
abstract: Prior studies in small mammals have shown that local epicardial application of inotropic compounds drives myocardial contractility without systemic side effects. Myocardial capillary blood flow, however, may be more significant in larger species than in small animals. We hypothesized that bulk perfusion in capillary beds of the large mammalian heart not only enhances drug distribution after local release, but also clears more drug from the tissue target than in small animals. Epicardial (EC) drug releasing systems were used to apply epinephrine to the anterior surface of the left heart of swine in either point-sourced or distributed configurations. Following local application or intravenous (IV) infusion at the same dose rates, hemodynamic responses, epinephrine levels in the coronary sinus and systemic circulation, and drug deposition across the ventricular wall, around the circumference and down the axis, were measured. EC delivery via point-source release generated transmural epinephrine gradients directly beneath the site of application extending into the middle third of the myocardial thickness. Gradients in drug deposition were also observed down the length of the heart and around the circumference toward the lateral wall, but not the interventricular septum. These gradients extended further than might be predicted from simple diffusion. The circumferential distribution following local epinephrine delivery from a distributed source to the entire anterior wall drove drug toward the inferior wall, further than with point-source release, but again, not to the septum. This augmented drug distribution away from the release source, down the axis of the left ventricle, and selectively toward the left heart follows the direction of capillary perfusion away from the anterior descending and circumflex arteries, suggesting a role for the coronary circulation in determining local drug deposition and clearance. The dominant role of the coronary vasculature is further suggested by the elevated drug levels in the coronary sinus effluent. Indeed, plasma levels, hemodynamic responses, and myocardial deposition remote from the point of release were similar following local EC or IV delivery. Therefore, the coronary vasculature shapes the pharmacokinetics of local myocardial delivery of small catecholamine drugs in large animal models. Optimal design of epicardial drug delivery systems must consider the underlying bulk capillary perfusion currents within the tissue to deliver drug to tissue targets and may favor therapeutic molecules with better potential retention in myocardial tissue.
authors.affiliation: Department of Anesthesiology and Pain Medicine, Steward St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. Electronic address: mikhail.maslov@steward.org.
authors.forename: Mikhail Y
authors.initials: MY
authors.lastname: Maslov
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: ere@mit.edu.
authors.forename: Elazer R
authors.initials: ER
authors.lastname: Edelman
authors.affiliation: Department of Anesthesiology and Pain Medicine, Steward St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. Electronic address: matthew.pezone@steward.org.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Pezone
authors.affiliation: Department of Anesthesiology and Pain Medicine, Steward St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. Electronic address: ewei@une.edu.
authors.forename: Abraham E
authors.initials: AE
authors.lastname: Wei
authors.affiliation: Department of Anesthesiology and Pain Medicine, Steward St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. Electronic address: Matthew.Wakim@bmc.org.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Wakim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Steward St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. Electronic address: mrmcapecod@gmail.com.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Murray
authors.affiliation: Department of Surgery, Steward St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. Electronic address: Hisashi.Tsukada@steward.org.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tsukada
authors.affiliation: Department of Surgery, Steward St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. Electronic address: GerogiannisI@southcoast.org.
authors.forename: Iraklis S
authors.initials: IS
authors.lastname: Gerogiannis
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: AGroothuis@mitralign.com.
authors.forename: Adam
authors.initials: A
authors.lastname: Groothuis
authors.affiliation: Department of Anesthesiology and Pain Medicine, Steward St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA. Electronic address: mark.lovich@steward.org.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lovich
mesh_terms: D000464:Alginates; D000818:Animals; D002196:Capillaries / Q000187:drug effects; D003326:Coronary Circulation / Q000502:physiology*; D016503:Drug Delivery Systems; D004837:Epinephrine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D005079:Excipients; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000378:metabolism; D007262:Infusions, Intravenous; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010496:Pericardium / Q000378:metabolism*; D020442:Poloxamer; D013552:Swine; D014018:Tissue Distribution; D014662:Vasoconstrictor Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000464:Alginates; D005079:Excipients; D014662:Vasoconstrictor Agents; D020442:Poloxamer; D004837:Epinephrine
keywords: Contractility; Epicardial drug delivery; Inotrope; Myocardial drug distribution; Systemic vascular resistance