Membrane transporter/receptor-targeted prodrug design: strategies for human and veterinary drug development

Abstract

The bioavailability of drugs is often severely limited due to the presence of biological barriers in the form of epithelial tight junctions, efflux proteins and enzymatic degradation. Physicochemical properties, such as lipophilicity, molecular weight, charge, etc., also play key roles in determining the permeation properties of drug candidates. As a result, many potential drug candidates may be dropped from the initial screening portfolio. Prodrug derivatization targeting transporters and receptors expressed on mammalian cells holds tremendous potential. Enhanced cellular delivery can significantly improve drug absorption. Such approaches of drug targeting and delivery have been the subject of intense research. Various prodrugs have been designed that demonstrate enhanced bioavailability and tissue specificity. This approach is equally applicable to human and veterinary pharmaceuticals since most of the transporters and receptors expressed by human tissues are also expressed in animals. This review highlights studies conducted on the use of transporters and receptors in an effort to improve drug bioavailability and to develop targeted drug delivery systems.

Introduction

Trends in the drug discovery sector indicate that out of every 9000–10,000 compounds that are selected as potential candidates, only 1 on average makes it to the market [1]. A large number of the developmental drug candidates may be very effective therapeutically but are often dropped from the screening stage as these compounds may not possess the optimal physicochemical properties needed to efficiently overcome biological barriers. Epithelial cells of mammalian organs and tissues (e.g., gastro-intestinal [GI], corneal, brain, lungs) constitute the principal barrier to cellular uptake and transport [2], [3], [4], [5], [6], [7]. Intestinal epithelial cells are of particular significance since they may limit the efficacy of orally administered drugs. These cells, like other epithelial cells, form tight junctions, limiting the paracellular flux of drug molecules. Thus, for a drug to be well absorbed from the GI tract, it needs to possess optimum physicochemical properties in order to permeate the epithelial cells by transcellular diffusion [8]. Besides the diffusional barrier caused by epithelial cell tight junctions, efflux pumps, such as the multidrug-resistance proteins (MDRs) [9] that are expressed on the apical side of the epithelial cells, further limit transcellular penetration. New variants and subtypes of these protein families continue to be discovered, challenging the drug delivery scientists to devise new means of transporting xenobiotics across epithelial cells.

Drug delivery in the veterinary arena is also a challenging task, not only because of the factors discussed above, but also due to the large number of species involved and the associated interspecies variation [8], [10], [11]. Such diversity is observed relative to drug disposition kinetics, the expression of metabolic enzymes, and the activity and specificity of the targeted drug. Anatomical differences can also complicate veterinary drug delivery. Moreover, owner compliance is another source of variability that can alter drug response. Taking all these factors into consideration, one can appreciate that veterinary drug delivery is at least as complicated as drug delivery in humans.

Within this review, we highlight some of the strategies that may be adopted to enhance drug transport across cellular barriers as a mechanism for increasing product oral bioavailability and to enhance drug uptake by specific target tissues.