Biomaterial Database

Topical delivery of a model phenolic drug: alkyloxycarbonyl prodrugs of acetaminophen. 2004

Scott C Wasdo, and Kenneth B Sloan

Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, USA.

OBJECTIVE To determine whether the delivery of a phenolic parent drug by its alkyloxycarbonyl (AOC) prodrugs through hairless mouse skin would show similar dependencies on water and lipid solubilities that similar prodrugs of more polar heterocyclic amide and imide parent drugs have shown. METHODS Flux through hairless mouse skin from suspensions in isopropyl myristate (J(MIPM)), solubilities in IPM (S(IPM)) and water (S(AQ)), and partition coefficients between isopropyl myristate (IPM) and pH 4.0 buffer (K(IPM:4.0)) were measured for two series of AOC derivatives of acetaminophen (APAP); their solubilities in pH 4.0 buffer (S4.0) were estimated from S(IPM)/K(IPM:4.0). Log J(MIPM) values were calculated from the n = 43 coefficients for the parameters in the transformed Potts-Guy (Roberts-Sloan) equation, and the average error of prediction (delta log J'(IPM)) was calculated. The J(MIPM), S(IPM), S4.0, and molecular weight (MW) data for this series and two other series were combined with the n = 43 database to give a n = 61 database, and new best fit coefficients were determined for the Roberts-Sloan equation: log J(MIPM) = x + y log S(IPM) + (1 - y) log S4.0 - z MW. RESULTS All of the 4-AOC-APAP derivatives underperformed based on their predicted log J(MIPM) (delta log J'(MIPM) = 0.275 +/- 0.147 log units) and, although the two more water soluble members of this more lipid soluble series were more effective than APAP, they were only marginally so: <2 times. Addition of three new series to the n = 43 database for the Roberts-Sloan equation did not substantially change the coefficients to the parameters: x, y, z, and r2 = -0.322, 0.530, 0.00337 and 0.92, respectively. CONCLUSIONS The topical delivery of a model phenolic drug by its AOC prodrugs through hairless mouse skin from IPM shows the same dependence on S(IPM), S4.0, and MW as the delivery of polar heterocycles by their similar prodrugs.

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
D009682	Magnetic Resonance Spectroscopy	Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (MAGNETIC RESONANCE IMAGING).	In Vivo NMR Spectroscopy,MR Spectroscopy,Magnetic Resonance,NMR Spectroscopy,NMR Spectroscopy, In Vivo,Nuclear Magnetic Resonance,Spectroscopy, Magnetic Resonance,Spectroscopy, NMR,Spectroscopy, Nuclear Magnetic Resonance,Magnetic Resonance Spectroscopies,Magnetic Resonance, Nuclear,NMR Spectroscopies,Resonance Spectroscopy, Magnetic,Resonance, Magnetic,Resonance, Nuclear Magnetic,Spectroscopies, NMR,Spectroscopy, MR
D010539	Permeability	Property of membranes and other structures to permit passage of light, heat, gases, liquids, metabolites, and mineral ions.	Permeabilities
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
D004058	Diffusion	The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially FACILITATED DIFFUSION, is a major mechanism of BIOLOGICAL TRANSPORT.	Diffusions
D004355	Drug Stability	The chemical and physical integrity of a pharmaceutical product.	Drug Shelf Life,Drugs Shelf Lives,Shelf Life, Drugs,Drug Stabilities,Drugs Shelf Life,Drugs Shelf Live,Life, Drugs Shelf,Shelf Life, Drug,Shelf Live, Drugs,Shelf Lives, Drugs
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