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Metal coordinated pharmaceuticals: a new technology for improved PK properties

corresponding

Thomas Piccariello1*,John Price1, Robert Oberlender1,Scott Palmer2, Torkel Gren3
*Corresponding author
1. Synthonics, Blacksburg, USA
2. Rush University Medical Center, Chicago, USA
3. Recipharm AB, Stockholm, Sweden

Abstract

Metal coordination complexes differ from salt forms due to the nature of bonding between the component atoms. While salts form ionic bonds, coordination complexes retain partial covalent characteristics arising from nephelauxetic (“cloud expanding”) effects. The effect of coordination chemistry on drug action is the premise of Synthonics’ metal coordinated pharmaceuticals (MCPs). This article introduces the metal coordination concept and discusses its use to improve the pharmacokinetic (PK) parameters of two well-known drugs. It describes the improved treatment of Parkinson’s disease by controlling and extending the release of levodopa into the blood from orally administered bismuth subdopate (BSD), a complex of bismuth and levodopa. The article also explores the use of metal coordination to reduce the inter-subject variability of absorption of furosemide, a widely used diuretic agent.


INTRODUCTION

Metal coordination entails attaching a pharmaceutically acceptable metal, such as zinc, bismuth or magnesium, to a known pharmaceutical agent to create a new and more effective drug.  Metal coordination chemistry can be used to enhance absorption via particular routes of administration, extend or control a drug’s release characteristics or to prevent a drug’s systemic absorption (2). The addition of the metal changes the way the drug is absorbed or delivered without altering the action of the underlying drug. 

Metal coordination is a flexible and inexpensive tool with broad application. It can be used to achieve a variety of outcomes as varying the metals used and the way they are attached allows one to “dial in” the desired PKs. In addition, the inclusion within the drug-metal complex of a wide variety of potential ligands enables ancillary drug performance enhancement. Many drugs are good candidates for metal coordination: a review of approximately 3,000 listed drugs found that over 400 had structures that allow metal coordination. Because the chemistry is relatively efficient and inexpensive to practice, compounds can often be dev ...




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