Inhibition of skin sphingosine synthesis: enhanced percutaneous permeation of 5-fluorouracil.
The present study was designed to investigate the role of skin sphingosine inhibition in enhancing the transcutaneous permeation of 5-fluorouracil (5-FU), a hydrophilic drug, across rat skin. Ethanol-perturbation significantly reduced the sphingosine content as compared to that in normal skin until 24 h of perturbation (p < 0.05). To maintain the low content of sphingosine for a longer time, beta-chloroalanine (beta-CA), a selective inhibitor of serine palmitoyl transferase, was used for inhibiting the sphingosine synthesis in viable skin. Application of beta-CA (600 microg or 1200 microg/7 cm2) to viable skin perturbed with ethanol significantly reduced the sphingosine content until 48 h as compared to that in perturbed viable skin (p < 0.05). However, the sphingosine content in viable skin perturbed with ethanol and treated with lower doses (200 or 400 microg/7 cm2) of beta-CA, returned significantly close to that in ethanol-perturbed viable skin at 36 h (p < 0.05). Skin sphingosine synthesis inhibition efficacy of 1200 microg beta-CA was insignificantly different to that of 600 microg dose of beta-CA at 36 h or 48 h (p < 0.05). The systemic delivery of percutaneously applied 5-FU across ethanol-perturbed rat skin treated with either 600 microg or 1200 microg beta-CA was significantly greater as compared to that obtained after oral administration or after application of lower percutaneous doses of beta-CA (p < 0.05). Higher Cmax, MRT, AUC and maintenance of effective plasma concentration of 5-FU for 46 h was achieved by a single topical application of a formulation containing 5-FU and 600 microg beta-CA to ethanol-perturbed skin.
Gupta
M
M
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India.
Mahajan
A
A
Babita
Gupta
S
S
Tiwary
A K
AK
D000284:Administration, Oral; D000818:Animals; D000963:Antimetabolites / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D051381:Rats; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012869:Skin Absorption; D012997:Solvents; D013110:Sphingosine / Q000096:biosynthesis*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000963:Antimetabolites; D004791:Enzyme Inhibitors; D012997:Solvents; D015091:beta-Alanine; C006977:3-chloroalanine; D013110:Sphingosine; D005472:Fluorouracil