Topical delivery of a model phenolic drug: alkyloxycarbonyl prodrugs of acetaminophen.
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.
Wasdo
Scott C
SC
Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, USA.
Sloan
Kenneth B
KB
D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000279:Administration, Cutaneous; D000818:Animals; D004058:Diffusion / Q000187:drug effects; D015194:Diffusion Chambers, Culture; D016503:Drug Delivery Systems / Q000379:methods; D004355:Drug Stability; D005260:Female; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D008812:Mice, Hairless; D010539:Permeability / Q000187:drug effects; D010636:Phenols / Q000138:chemical synthesis / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects / Q000502:physiology; D012995:Solubility / Q000187:drug effects; D013678:Technology, Pharmaceutical / Q000379:methods
D010636:Phenols; D011355:Prodrugs; D000082:Acetaminophen