Permeability profiles of M-alkoxysubstituted pyrrolidinoethylesters of phenylcarbamic acid across caco-2 monolayers and human skin.
OBJECTIVE
The purpose of the present research was to study 10 m-alkoxysubstituted pyrrolidinoethylesters of phenylcarbamic acid-potential local anesthetics. The relationships between the structure of the molecule, its physicochemical parameters (log D(oct), log k, R(M), solubility) were correlated to the permeability data obtained from permeation experiments in Caco-2 monolayers and excised human skin in vitro.


METHODS
The extent and mechanism(s) of permeability of the series were studied through a Caco-2 monolayer in the apical-to-basolateral (a-b) and basolateral-to-apical (b-a) directions. The MTT test was performed to determine cellular damage. In vitro transdermal permeability data were obtained from permeation experiments on excised human skin by using side-by-side chambers. Passive diffusion and iontophoretically enhanced permeability were measured.


RESULTS
In Caco-2 monolayers, similar results in the shape of the permeability curves were obtained for the two directions. In the b-a direction, the values of P(app) were approximately 2-6 times greater than in the a-b direction. A plot of drug permeability vs. the number of carbons in the alkoxychain plateaued first, after which the permeability decreased by the increasing lipophilicity of the drug. If the log D(oct) of the ester was > or = 3.4 and the MW > 385 Da, no measurable Caco-2 permeability was found. Cell damage was also higher by the more lipophilic compounds. In excised human skin, the relationship between the passive diffusion of the drugs and the number of carbons in the alkoxychain was parabolic (r2 = 0.95). Introducing low-level electrical current (iontophoresis), transdermal permeability of the more hydrophilic phenylcarbamic acid esters increased clearly.


CONCLUSIONS
Lipophilicity and solubility of a compound have crucial roles in the permeation process. A very high lipophilicity has, however, a negative influence on the permeability, both intestinally and transdermally. Iontophoresis significantly increases the diffusion of small and less lipophilic compounds.
Gyürösiová
Lenka
L
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Bratislava, Slovakia.
Laitinen
Leena
L
Raiman
Johanna
J
Cizmárik
Jozef
J
Sedlárová
Eva
E
Hirvonen
Jouni
J
D000279:Administration, Cutaneous; D000465:Algorithms; D018938:Caco-2 Cells; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D004952:Esters / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007478:Iontophoresis; D008970:Molecular Weight; D010539:Permeability; D012869:Skin Absorption / Q000502:physiology*; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles
D002219:Carbamates; D004952:Esters; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue