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Prodrugs of nucleoside analogues for improved oral absorption and tissue targeting

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ABSTRACT

Nucleoside analogues are widely used for the treatment of antiviral infections and anticancer chemotherapy. However, many nucleoside analogues suffer from poor oral bioavailability due to their high polarity and low intestinal permeability. In order to improve oral absorption of these polar drugs, prodrugs have been employed to increase lipophilicity by chemical modification of the parent. Alternatively, prodrugs targeting transporters present in the intestine have been exploited to facilitate the transport of the nucleoside analogues. Valacyclovir and valganciclovir are two successful valine ester prodrugs transported by the PepT1 transporter. Recently, research efforts have focused on design of prodrugs for tissue specific delivery to improve efficacy and safety. This review presents advances of prodrug approaches for improved oral absorption of nucleoside analogues and recent developments in tissue targeting. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1109–1134, 2008

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INTRODUCTION

Nucleosides are building blocks of RNA and DNA. Nucleoside analogues are synthetic compounds that are structurally similar to natural nucleosides. Many nucleoside analogues have antiviral and antitumor properties. Over the last two decades, numerous nucleoside analogues and their prodrugs were developed for the treatment of patients with infections of human immunodeficiency virus (HIV), including zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir,

RATIONALE FOR PRODRUG DESIGN

For orally administered drugs, the intestinal epithelial membrane forms the first barrier to drug absorption. Therefore, for a drug to be well absorbed in the gastrointestinal tract, it needs to possess optimum physicochemical properties in order to cross the epithelial membrane by passive diffusion. Prodrug strategies are typically employed to alter lipophilicity, permeability, stability, and tissue specificity of the active drugs and thus improve drug delivery properties over the parent drug.

SCREENING PARADIGMS FOR PRODRUGS

The effectiveness of a prodrug is typically evaluated by characterization of physicochemical properties, assessment of Caco‐2 cell permeabilities and determination of pharmacokinetics (PK) and exposures in animals. Considering the data from these screening studies and additional factors, such as, ease of synthesis, cost, and toxicity of the promoiety, lead prodrugs are selected for further evaluation. Figure 2 shows the screening paradigm used in our lab for prodrugs intended to improve oral

Prodrugs of Acyclic Nucleoside Analogues

Acyclovir, ganciclovir, penciclovir, and H2G are acyclic guanosine nucleoside analogues and have potent antiviral activities (Fig. 3). They are selectively phosphorylated to the monophosphate level by a virus specified thymidine kinase and subsequently converted to di‐ and triphosphates by cellular kinases.72., 73., 74. After phosphorylation, the triphosphates either incorporate into the viral DNA resulting in chain termination or slow the elongation of viral DNA and therefore, inhibit the

CONCLUSION

Drug development efforts have been made to continually identify new therapeutic agents and prodrugs with desired drug‐like characteristics, improved therapeutic efficacy and less adverse effects. For orally administered drugs, the intestinal epithelial membrane forms the first barrier to drug absorption. Most oral drugs are absorbed into systemic circulation by passive diffusion across the intestinal epithelial membrane. Since nucleoside analogues are polar molecules and have limited membrane

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