Analysis of in vitro skin permeation of 22-oxacalcitriol having a complicated metabolic pathway.
OBJECTIVE
The purpose of this study is to analyze simultaneous skin permeation and metabolism of 22-oxacalcitriol (OCT) having several metabolites in skin by observing skin permeation of only unchanged OCT through excised rat skin.


METHODS
A diffusion model including metabolic processes was employed to express simultaneous skin permeation and metabolism of OCT. In vitro permeation experiments of OCT from Oxarol ointment through full-thickness and stripped rat skin were carried out using Franz-type diffusion cells. Time courses of unchanged OCT amounts in ointment, skin, and receptor fluid were determined and fitted to diffusion equations to obtain permeation parameters and a metabolic rate.


RESULTS
Fitting curves of the skin permeation profile obtained by the model were sufficiently close to observed data of unchanged OCT amounts in ointment, skin, and receptor fluid. The following parameters were obtained: metabolic rate of 1.37 x 10(-1) h(-1), and diffusion constants of OCT in stratum corneum (SC) (D(SC)) and viable epidermis and dermis (VED) (D(VED)) of 1.50 x 10(-7) and 2.96 x 10(-4) cm2/h, respectively. The partition coefficient of OCT for SC/ointment (K(SC/D)) was 7 times greater than that of VED/ointment (K(VED/D)).


CONCLUSIONS
The present analysis made it possible to calculate skin permeation parameters (partitioning, diffusivity, and metabolic rate) of OCT without requiring metabolic information, e.g., quantification of metabolites or identification of metabolic pathways. This would be widely applicable for drugs that are not suitable for conventional methods due to complicated metabolic pathways.
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan. yamaguchikuj@chugai-pharm.co.jp
Koji
K
Yamaguchi
Tetsuya
T
Mitsui
Toshinori
T
Yamamoto
Rie
R
Shiokawa
Yuko
Y
Nomiyama
Norihisa
N
Ohishi
Yoshinori
Y
Aso
Kenji
K
Sugibayashi
D000465:Algorithms; D000818:Animals; D001711:Biotransformation; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003879:Dermatologic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D020405:Dermis / Q000378:metabolism; D004058:Diffusion; D015194:Diffusion Chambers, Culture; D004817:Epidermis / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D012869:Skin Absorption / Q000502:physiology*
D003879:Dermatologic Agents; D002117:Calcitriol; C051883:maxacalcitol