Monohydroxylation and esterification as determinants of the effects of cis- and trans-9-octadecenoic acids on the permeation of hydrocortisone and 5-fluorouracil across hairless mouse skin in vitro.
The effects of cis-9-octadecenoic acid (oleic acid) and of a group of chemically related cis- (ricinoleic acid) and trans- (ricinelaidic acid) 12-monohydroxylated derivatives and their corresponding ethyl and methyl esters on the skin permeation of model hydrophobic (hydrocortisone, log K=1.61) and hydrophilic (5-fluorouracil, log K=-0.89) drugs was investigated in vitro using excised hairless mouse skin. Drug solutions were prepared in propylene glycol, with and without the addition of a fatty acid to a level of 5%. Whereas the addition of oleic acid markedly enhanced the transdermal flux of both drugs relative to a sample in propylene glycol alone (hydrocortisone approximately 1800-fold; 5-fluorouracil approximately 330-fold), that of a cis- or trans-12-monohydroxylated analog of oleic acid resulted in only a small increase (1.4-2.7-fold for hydrocortisone; 4.4-6.6-fold for 5-fluorouracil). On the other hand, the methyl and ethyl esters of cis- and trans-12-hydroxy-9-octadecenoic acid exerted a much greater enhancing effect (327-720-fold for hydrocortisone, 42-74-fold for 5-fluorouracil) than the corresponding parent fatty acids. Furthermore, whereas the ethyl esters were found to have a greater effect on the skin permeation of hydrocortisone than the methyl esters, the reverse was true with regards to 5-fluorouracil. Additionally, the esters of trans-12-hydroxy-9-octadecenoic acid promoted permeation to an extent comparable to that achieved with their cis-counterparts.
Song
J F
JF
St. John's University, College of Pharmacy and Allied Health Professions, Jamaica, NY 11439, USA.
Lau-Cam
C A
CA
Kim
K H
KH
D000818:Animals; D004952:Esters / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006854:Hydrocortisone / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D051379:Mice; D008812:Mice, Hairless; D019301:Oleic Acid / Q000494:pharmacology*; D010539:Permeability; D012277:Ricinoleic Acids / Q000494:pharmacology*; D012867:Skin / Q000378:metabolism*
D004952:Esters; D012277:Ricinoleic Acids; D019301:Oleic Acid; C030521:ricinoleic acid; D005472:Fluorouracil; D006854:Hydrocortisone