Prodrugs--from Serendipity to Rational Design

School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Pharmacological reviews (Impact Factor: 17.1). 09/2011; 63(3):750-71. DOI: 10.1124/pr.110.003459
Source: PubMed


The prodrug concept has been used to improve undesirable properties of drugs since the late 19th century, although it was only at the end of the 1950s that the actual term prodrug was introduced for the first time. Prodrugs are inactive, bioreversible derivatives of active drug molecules that must undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then elicit its desired pharmacological effect in the body. In most cases, prodrugs are simple chemical derivatives that are only one or two chemical or enzymatic steps away from the active parent drug. However, some prodrugs lack an obvious carrier or promoiety but instead result from a molecular modification of the prodrug itself, which generates a new active compound. Numerous prodrugs designed to overcome formulation, delivery, and toxicity barriers to drug utilization have reached the market. In fact, approximately 20% of all small molecular drugs approved during the period 2000 to 2008 were prodrugs. Although the development of a prodrug can be very challenging, the prodrug approach represents a feasible way to improve the erratic properties of investigational drugs or drugs already on the market. This review introduces in depth the rationale behind the use of the prodrug approach from past to present, and also considers the possible problems that can arise from inadequate activation of prodrugs.

    • "The problem of active, or more active, metabolites should be fully integrated in any environmental ecotoxicology assessment of pharmaceuticals. Prodrugs are often used in chemotherapy, e.g., Miproxifene Phosphate, Capecitabine, Captopril, Cyclophosphamide, Sulfasalazine, Loperamide, Fosphenytoin, and Bambuterol (Huttunen et al., 2011; Rautio et al., 2008; Stacher et al., 1992), and also in several other treatments against nausea, convulsion, anaesthesia, inflammation, etc., such as valganciclovir, sulindac, prednisolone phosphate, and propofol phosphate (Banaszczyk et al., 2002). They improve pharmaceutical absorption, limit side effects and increase the selectivity of target cells. "
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    ABSTRACT: Although pharmaceutical metabolites are found in the aquatic environment, their toxicity on living organisms is poorly studied in general. Endoxifen and 4-hydroxy-tamoxifen (4OHTam) are two metabolites of the widely used anticancer drug tamoxifen for the prevention and treatment of breast cancers. Both metabolites have a high pharmacological potency in vertebrates, attributing prodrug characteristics to tamoxifen. Tamoxifen and its metabolites are body-excreted by patients, and the parent compound is found in sewage treatment plan effluents and natural waters. The toxicity of these potent metabolites on non-target aquatic species is unknown, which forces environmental risk assessors to predict their toxicity on aquatic species using knowledge on the parent compounds. Therefore, the aim of this study was to assess the sensitivity of two generations of the freshwater microcrustacean Daphnia pulex towards 4OHTam and endoxifen. Two chronic tests of 4OHTam and endoxifen were run in parallel and several endpoints were assessed. The results show that the metabolites 4OHTam and endoxifen induced reproductive and survival effects. For both metabolites, the sensitivity of D. pulex increased in the second generation. The intrinsic rate of natural increase (r) decreased with increasing 4OHTam and endoxifen concentrations. The No-Observed Effect Concentrations (NOECs) calculated for the reproduction of the second generation exposed to 4OHTam and endoxifen were <1.8 and 4.3μg/L, respectively, whereas the NOECs that were calculated for the intrinsic rate of natural increase were <1.8 and 0.4μg/L, respectively. Our study raises questions about prodrug and active metabolites in environmental toxicology assessments of pharmaceuticals. Our findings also emphasize the importance of performing long-term experiments and considering multi-endpoints instead of the standard reproduction outcome. Copyright © 2015 Elsevier B.V. All rights reserved.
    No preview · Article · Jul 2015 · Science of The Total Environment
    • "Brentford, UK). The bioavailability of valacyclovir is two times higher than acyclovir due to its higher solubility and active transport via amino acid receptors [26]. After intracellular absorption, valacyclovir is hydrolyzed, generating acyclovir, which requires activation by viral thymidine kinase and cellular kinases to finally inhibit herpes virus DNA polymerase. "
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    ABSTRACT: Water solubility is a key parameter in drug formulation since it highly influences drug pharmacokinetics and pharmacodynamics. In the past decades, the challenge with poorly water soluble drugs has been growing continuously. As a matter of fact, poorly soluble compounds represent 40% of the top 200 oral drugs marketed in the US, 33% of drugs listed in the US Pharmacopeia, 75% of compounds under development and 90% of new chemical entities. The present article presents and discusses the pharmaceutical strategies available to overcome poor water solubility in light of final drug product examples. First, chemical modifications based on the adjustment of the pH and the design of prodrugs are presented and discussed. Physical modifications based on modified solid states of the drug, small drug particles, cosolvents, surfactants, lipids and cyclodextrins are discussed in a second part. Finally, the option of modifying the route of administration is briefly presented.
    No preview · Article · May 2015 · Journal of Drug Delivery Science and Technology
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