In vitro evaluation of alkylcarbonyloxymethyl (ACOM) ethers as novel prodrugs of phenols for topical delivery: ACOM prodrugs of acetaminophen. 2008

Joshua D Thomas, and Kenneth B Sloan
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, NCI-Frederick, Frederick, MD 21702, USA.

The fluxes (J(IPM)) of a series of alkylcarbonyloxymethyl (ACOM) ethers of acetaminophen (APAP) were measured through hairless mouse skin from suspensions of each prodrug in isopropyl myristate (IPM). Solubilities in IPM, estimated solubilities in pH 4.0 buffer (S(4.0)) and flux data for the 4-ACOM-APAP prodrugs were incorporated into the Roberts-Sloan (RS) database to give new estimates for the independent variables of the RS equation: logJ(IPM)=x+ylogS(IPM)+(1-y)logS(4.0)-zM(W). All but one of the 4-ACOM-APAP derivatives hydrolyzed completely on permeation through mouse skin. Three out of the five prodrugs permeated the skin better than APAP, with a maximum fourfold increase in flux. Biphasic solubility - not solubility in a single solvent - was shown to have the greatest impact on flux. A fit of the new n=66 database to the RS equation gave the following values for x, y, z, and r(2): x=-0.545, y=0.511, z=0.00253, r(2)=0.915. These results demonstrate that the topical delivery of a model phenol, acetaminophen, can be improved by transiently masking the phenolic hydroxyl group as an ACOM ether.

UI MeSH Term Description Entries
D008812 Mice, Hairless Mutant strains of mice that produce little or no hair. Hairless Mice,Mice, Inbred HRS,Mice, hr,Hairless Mouse,Mice, HRS,Mouse, HRS,Mouse, Inbred HRS,HRS Mice,HRS Mice, Inbred,HRS Mouse,HRS Mouse, Inbred,Inbred HRS Mice,Inbred HRS Mouse,Mouse, Hairless
D008954 Models, Biological Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment. Biological Model,Biological Models,Model, Biological,Models, Biologic,Biologic Model,Biologic Models,Model, Biologic
D010636 Phenols Benzene derivatives that include one or more hydroxyl groups attached to the ring structure.
D011355 Prodrugs A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug. Drug Precursor,Drug Precursors,Pro-Drug,Prodrug,Pro-Drugs,Precursor, Drug,Precursors, Drug,Pro Drug,Pro Drugs
D004987 Ethers Organic compounds having two alkyl or aryl groups bonded to an oxygen atom, as in the formula R1–O–R2.
D005260 Female Females
D000082 Acetaminophen Analgesic antipyretic derivative of acetanilide. It has weak anti-inflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage. Acetamidophenol,Hydroxyacetanilide,Paracetamol,APAP,Acamol,Acephen,Acetaco,Acetominophen,Algotropyl,Anacin-3,Datril,N-(4-Hydroxyphenyl)acetanilide,N-Acetyl-p-aminophenol,Panadol,Tylenol,p-Acetamidophenol,p-Hydroxyacetanilide,Anacin 3,Anacin3
D000279 Administration, Cutaneous The application of suitable drug dosage forms to the skin for either local or systemic effects. Cutaneous Drug Administration,Dermal Drug Administration,Drug Administration, Dermal,Percutaneous Administration,Skin Drug Administration,Transcutaneous Administration,Transdermal Administration,Administration, Dermal,Administration, Transcutaneous,Administration, Transdermal,Cutaneous Administration,Cutaneous Administration, Drug,Dermal Administration,Drug Administration, Cutaneous,Skin Administration, Drug,Administration, Cutaneous Drug,Administration, Dermal Drug,Administration, Percutaneous,Administrations, Cutaneous,Administrations, Cutaneous Drug,Administrations, Dermal,Administrations, Dermal Drug,Administrations, Percutaneous,Administrations, Transcutaneous,Administrations, Transdermal,Cutaneous Administrations,Cutaneous Administrations, Drug,Cutaneous Drug Administrations,Dermal Administrations,Dermal Drug Administrations,Drug Administrations, Cutaneous,Drug Administrations, Dermal,Drug Skin Administrations,Percutaneous Administrations,Skin Administrations, Drug,Skin Drug Administrations,Transcutaneous Administrations,Transdermal Administrations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012867 Skin The outer covering of the body that protects it from the environment. It is composed of the DERMIS and the EPIDERMIS.

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