Analysis of simultaneous transport and metabolism of ethyl nicotinate in hairless rat skin.
OBJECTIVE
Simultaneous skin transport and metabolism of ethyl nicotinate (EN), a model drug, were measured and theoretically analyzed.


METHODS
Several permeation studies of EN or its metabolite nicotinic acid (NA) were done on full-thickness skin or stripped skin with and without an esterase inhibitor. Permeation parameters such as partition coefficient of EN from the donor solution to the stratum corneum and diffusion coefficients of EN and NA in the stratum corneum and the viable epidermis and dermis were determined by these studies. Enzymatic parameters (Michaelis constant Km and maximum metabolism rate Vmax) were obtained from the production rate of NA from different concentrations of EN in the skin homogenate. Obtained permeation data were then analyzed by numerical method based on differential equations showing Fick's second law of diffusion in the stratum corneum and the law with Michaelis-Menten metabolism in the viable epidermis and dermis.


RESULTS
Fairly good steady-state fluxes of EN and NA through the skin were obtained after a short lag time for all the concentrations of EN applied. These steady-state fluxes were not proportional to the initial donor concentration of EN: EN and NA curves were concave and convex, respectively, which suggests that metabolic saturation from EN to NA takes place in the viable skin at higher EN application. The steady-state fluxes of EN and NA calculated by the differential equations with resulting permeation and enzymatic parameters were very close to the obtained data.


CONCLUSIONS
The present method is a useful tool to analyze simultaneous transport and metabolism of many drugs and prodrugs, especially those showing Michaelis-Menten type-metabolic saturation in skin.
Sugibayashi
K
K
Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan.
Hayashi
T
T
Hatanaka
T
T
Ogihara
M
M
Morimoto
Y
Y
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001711:Biotransformation; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004058:Diffusion; D004950:Esterases / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D007531:Isoflurophate / Q000494:pharmacology; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009525:Niacin / Q000378:metabolism; D009539:Nicotinic Acids / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D012867:Skin / Q000378:metabolism*; D012869:Skin Absorption / Q000502:physiology*; D013056:Spectrophotometry, Ultraviolet
D002800:Cholinesterase Inhibitors; D009539:Nicotinic Acids; D007531:Isoflurophate; D009525:Niacin; D004950:Esterases; C037328:ethylnicotinate