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    Home > Medical News > Medical Research Articles > The influence of phosphate group on the drug-making properties of drugs

    The influence of phosphate group on the drug-making properties of drugs

    • Last Update: 2021-07-21
    • Source: Internet
    • Author: User
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    Phosphate is an important part of nucleic acid and exists in large quantities in the human body.
    It is an endogenous substance that is harmless to the human body.
    It can help drugs improve water solubility and transport into cells, so it is an excellent small molecule carrier

    It can even improve the biophysical and chemical properties of the drug, reduce toxic and side effects, and thereby improve the drug-making properties of the drug


    Currently marketed phosphate ester prodrugs mainly include antiviral drug adefovir dipivoxil (adefovir dipivoxil), tenofovir disoproxil fumarate (tenofovir disoproxil fumarate) and so on


    Due to limited space, this article introduces the influence of phosphate groups on the druggability of drugs from the following aspects



    Improve drug choice

    While traditional anti-tumor drugs kill tumor cells, they also attack normal tissue cells around them, so they generally have greater toxic side effects


    Studies have proved that the content of phosphatase in tumor cells is higher than that in normal cells, so pharmacologists envisaged making anti-tumor drugs into phosphate prodrugs to improve the delivery of their target organs

    When the anti-tumor drug enters the tumor tissue, it is hydrolyzed under the action of phosphatase to release the active anti-tumor drug, thereby increasing the concentration of the active ingredient in the tumor tissue, and relatively reducing the concentration in the normal tissue.
    Toxic side effects

    For example, the estramustine developed by Roche has poor selectivity for prostate cancer.
    The introduction of phosphoric acid ester group into estramustine has significantly improved selectivity for prostate cancer and reduced toxic and side effects



    Improve medication compliance

    On the basis of the original drug, the introduction of phosphate groups to make prodrugs can also reduce the discomfort caused to patients during administration to a certain extent, and improve their medication compliance

    For example, clindamycin injections generally cause severe pain, and oral administration tastes bitter and easily triggers gastrointestinal reactions.
    When clindamycin is made into clindamycin phosphate, the water solubility is improved.
    It can be administered by intravenous injection, and it is quickly hydrolyzed to clindamycin under the action of alkaline phosphatase in the blood, which avoids taste discomfort and gastrointestinal reactions caused by oral medication



    Improve water solubility

    There are many ways to change the water solubility of drugs, such as structural optimization, salt formation, and improvement of dosage forms

    The following example demonstrates that the introduction of phosphate groups can improve the water solubility of drugs by means of structural modification


    The anti-epileptic drug phenytoin has relatively low water solubility (24 μg·mL-1).
    The injection must first dissolve the original drug in 40% propylene glycol and 10% alcohol, and also need to adjust the pH of the solution to 12 to make it completely It dissolves, but phenytoin is precipitated due to the continuous drop of pH during intravenous injection, which will cause strong irritation to blood vessels and local tissues, and even necrosis

    In addition, propylene glycol has the ability to induce heparin resistance, and when phenytoin is combined with heparin, it can reduce the effectiveness of phenytoin

    Phosphate group is introduced on the basis of phenytoin, and the obtained fosphenytoin sodium increases the water solubility of the original drug (140 mg·m L-1).
    It can be made into an aqueous solution of 50 mg·m L-1 for intravenous Administration by means of injection or intramuscular injection greatly overcomes the adverse reactions caused by the clinical application of phenytoin and eliminates the drug-drug interaction of phenytoin


    In addition, the introduction of phosphate ester groups on the basis of the original drug can significantly improve the solubility of the original drug.
    Therefore, drug researchers introduce phosphate ester groups or make sodium salts into some poorly water-soluble drugs, thereby satisfying the clinical needs.
    Demand for injections

    For example, the adrenal cortex hormone betamethasone sodium phosphate and the anti-amebiasis drug metronidazole sodium phosphate are 70-200 times more water-soluble than the original drug.
    The former can be made into water injections, and the latter can be made into powder injections



    Improve bioavailability

    Anavir has strong antiviral activity and good drug resistance, and has strong inhibitory activity against HIV

    However, annavir has high lipophilicity (solubility of 0.
    04 mg·mL-1), which limits its bioavailability when administered as a crystalline solid.
    The pharmaceutical preparation must contain a higher proportion of organic excipients.
    To promote dissolution in the stomach

    Therefore, a single dose of the drug is usually administered in a soft capsule formula and multiple tablets, which brings inconvenience to the patient's medication

    After introducing the phosphate group into its structure, the water solubility and solid stability of fusanavir obtained are significantly improved.
    After being made into calcium salt tablets, it can be quickly absorbed by gastrointestinal epithelial cells and converted Anavir, the dose of 2 tablets is equivalent to 8 soft capsules of Anavir, which improves the bioavailability, reduces the dosage, and reduces the burden of medication on patients



    Improve fat solubility

    Stavudine (logP=-0.
    59) is a class of anti-HIV drugs with good selectivity.
    The drug needs to be converted into monophosphate compounds under the action of adenosine kinase, and then undergo diphosphorylation and triphosphorylation to achieve anti-HIV drugs.
    The pharmacological activity of the virus

    However, stavudine and its phosphorylation products are relatively polar, and it is difficult to reach the site of action

    In order to improve its fat solubility, drug researchers introduced phosphate groups in its structure, thereby greatly improving the fat solubility of the drug and the ability of the drug to penetrate cell membranes (logP=2.
    15), and at the same time, it also improved Stav Determine the degree of phosphorylation and selectivity


      to sum up

    The introduction of phosphate groups on the basis of the original drug not only improves the selectivity of the drug and reduces its side effects, but also improves the solubility, provides a variety of routes of administration, and greatly enhances the drug-making properties of the drug

    Therefore, when some simple pharmacological methods cannot improve the druggability of a drug, phosphorylation structure modification can be a way to improve the druggability of a drug



    Perry CM, etc.
    Estramustine Phosphate Sodium: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in prostate cancer.
    Drugs&Aging, 1995, 7 (1): 49-74,DOI: 10.
    2165/00002512-199507010-00006 .

    Heimbach Y, et al.
    Enzyme-mediated precipitation of parent drugs from their Phosphate prodrugs.
    International Journal of Pharmaceutics, 2003, 261(1-2): 81-92, DOI: 10.
    1016/s0378-5173(03) 00287-4.

    Plaisance KI, et al.
    Pharmacokinetic evaluation of two dosage regimens of clindamycin phosphate.
    Antimicrobial Agents and Chemherapy, 1989, 33(5): 618-620, DOI:10.

    Brouwers J, et al.
    In vitro behavior of a phosphate ester prodrug of amprenavir in human intestinal fluids and in the Caco-2 system: Illustration of intraluminal supersaturation.
    Pharmaceut, 2007, 336(2): 302-309, DOI: 10.

    5 Furman PA, et al.
    Phosphorylation of 3'-azido-3'-deoxythymidine and selective interaction of the 5'-triphosphate with human immunodeficiency virus reverse transcriptase.
    Proc Natl Acad Sci USA, 1986, 83: 8333-8337.
    DOI: 10.

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