Biomedical Engineering Reference
In-Depth Information
9
Prodrugs: Design
and Development
Anders Buur and Niels Mørk
CONTENTS
9.1 Introduction ......................................................................................................................... 135
9.2 The Prodrug Principle......................................................................................................... 136
9.3 Design of Prodrugs—Chemical Considerations................................................................. 137
9.3.1 Prodrugs Transformed by Enzymatic Reactions ................................................... 137
9.3.2 Prodrugs Transformed by Spontaneous Reactions ................................................ 138
9.4 Design of Prodrugs—Application of the Prodrug Principle............................................... 140
9.4.1 Design of Prodrugs with Improved Bioavailability ............................................... 140
9.4.1.1 Improved Aqueous Solubility................................................................. 141
9.4.1.2 Improved Biomembrane Permeability (Passive Diffusion).................... 141
9.4.1.3 Improved Transporter-Mediated Permeability....................................... 143
9.4.1.4 Increased Stability in the Gastrointestinal Tract.................................... 143
9.4.1.5 Improved Metabolic Stability................................................................. 144
9.4.2 Design of Prodrugs for Prolonged Drug Action .................................................... 146
9.4.2.1 Intramuscular Depot Injections.............................................................. 146
9.4.2.2 Macromolecular Prodrugs...................................................................... 146
9.4.3 Design of Produgs for Drug Targeting .................................................................. 146
9.5 Development of Prodrugs....................................................................................................148
9.5.1 Safety Assessment of Prodrugs.............................................................................. 148
9.6 Concluding Remarks........................................................................................................... 148
Further Readings ............................................................................................................................ 149
9.1 INTRODUCTION
Although it is well recognized that a clinically useful drug must possess balanced characteristics
in terms of efi cacy and safety as well as drugability, traditional drug discovery and design efforts
have not focused sufi ciently on the latter. Consequently, challenges concerning oral bioavailability,
pharmacokinetics, and pharmaceutical technical properties have only been dealt with during the
development phase, which in many cases has proven to be difi cult.
The inappropriateness of this old paradigm to drug design has become evident to the pharmaceu-
tical industry. The implementation of high-throughput screening and combinatorial chemistry have
led to the identii cation of numerous lead compounds with excellent pharmacological properties in
terms of afi nity and specii city but at the same time inadequate pharmaceutical, biopharmaceutical,
and absorption, distribution, metabolism, and excretion (ADME) properties such as low aqueous
solubility or high metabolic liability, thus resulting in a signii cant increase in the development time
and the cost or even the closure of projects.
135
