Comparative analysis of percutaneous absorption enhancement by d-limonene and oleic acid based on a skin diffusion model

Pharm Res. 1994 Mar;11(3):377-83. doi: 10.1023/a:1018904802566.


Percutaneous absorption-enhancing effects of d-limonene and oleic acid were investigated using three model drugs with different lipophilicities in in vitro diffusion experiments with guinea pig skin. Pretreatment of the skin with d-limonene resulted in a large penetration enhancement for the lipophilic butylparaben (BP) and amphiphilic 6-mercaptopurine (6-MP) but had little effect on the hydrophilic mannitol (MT). Oleic acid caused a large effect only on 6-MP penetration. The penetration profiles were analyzed with a two-layer skin diffusion model consisting of stratum corneum with polar and nonpolar routes and viable epidermis plus dermis. Through curve-fitting, six parameters corresponding to drug diffusivity and partitioning in these three regions of the skin were obtained, and the mechanisms of enhancers were assessed in comparison with those of 1-geranylazacycloheptan-2-one (GACH) reported previously. Increased penetration was caused mainly by modification of the barrier property of the nonpolar route in the stratum corneum in all cases. In the nonpolar route, d-limonene increased mainly drug diffusivity, while GACH enhanced predominantly drug partitioning. On the other hand, oleic acid moderately increased both parameters.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cyclohexenes
  • Diffusion
  • Guinea Pigs
  • In Vitro Techniques
  • Limonene
  • Male
  • Mannitol / pharmacokinetics
  • Mercaptopurine / pharmacokinetics
  • Models, Biological
  • Oleic Acid
  • Oleic Acids / pharmacokinetics*
  • Parabens / pharmacokinetics
  • Skin Absorption / physiology*
  • Terpenes / pharmacokinetics*


  • Cyclohexenes
  • Oleic Acids
  • Parabens
  • Terpenes
  • Oleic Acid
  • Mannitol
  • butylparaben
  • Limonene
  • Mercaptopurine