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Permeability Profiles of M-Alkoxysubstituted Pyrrolidinoethylesters of Phenylcarbamic Acid Across Caco-2 Monolayers and Human Skin

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Abstract

Purpose. 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 Doct, log k, RM, 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 Papp were ∼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 Doct of the ester was ≥ 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 (r 2 = 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.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojárov 10, 845 45, Bratislava, Slovakia

    Lenka Gyürösiová, Jozef Čižmárik & Eva Sedlárová

  2. Viikki Drug Discovery Technology Center, Department of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland

    Leena Laitinen, Johanna Raiman & Jouni Hirvonen

  3. Division of Pharmaceutical Technology, University of Helsinki, Finland

    Johanna Raiman

Authors
  1. Lenka Gyürösiová
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  2. Leena Laitinen
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  3. Johanna Raiman
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  4. Jozef Čižmárik
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  5. Eva Sedlárová
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  6. Jouni Hirvonen
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Correspondence to Jouni Hirvonen.

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Gyürösiová, L., Laitinen, L., Raiman, J. et al. Permeability Profiles of M-Alkoxysubstituted Pyrrolidinoethylesters of Phenylcarbamic Acid Across Caco-2 Monolayers and Human Skin. Pharm Res 19, 162–168 (2002). https://doi.org/10.1023/A:1014208515545

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