Percutaneous and systemic disposition of hexamethylene lauramide and its penetration enhancement effect on hydrocortisone in a rat sandwich skin-flap model.
The percutaneous absorption and distribution profile of hexamethylene lauramide (hexahydro-1-lauroyl-1H-azepine) were examined using a rat skin-flap model. After a topical dose to the skin flap, the drug concentrations in the vasculature at the site of drug application and in the systemic blood were monitored simultaneously. Hexamethylene lauramide penetrated the skin and reached a steady state in stratum corneum, viable epidermis, dermis, and cutaneous blood in 3 hr. Its concentration in the skin was much higher than that in the blood. Its apparent concentration in the epidermis was 19 times that in the dermis and about 3000 times that in the cutaneous blood. The percutaneous absorption of 14C-hexamethylene lauramide resulted in ascending systemic blood concentrations throughout the experimental period, whereas the cutaneous blood levels remained steady. The topically absorbed hexamethylene lauramide was quantitatively recovered in urine (85%) and feces (13%). The half-lives of urinary and fecal excretion of 14C-hexamethylene lauramide were 17 and 30 hr, respectively. Hexamethylene lauramide, when topically coadministered in an experimental formulation, enhanced the skin penetration of hydrocortisone with increased drug contents in the stratum corneum (2-fold) and with increased hydrocortisone concentrations in the cutaneous blood (3.4-fold) and the systemic blood (3.5-fold). The results indicated that the high concentration and retention of hexamethylene lauramide in stratum corneum and viable epidermis may contribute to its penetration enhancement effect in the skin. A steady state in percutaneous tissues was observed before the drug reached distribution equilibrium systemically. The systemic blood concentration of a topically applied agent therefore may not reflect its percutaneous kinetic processes before a systemic distribution equilibrium is reached.(ABSTRACT TRUNCATED AT 250 WORDS)
Tang-Liu
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DD
Department of Pharmacokinetics, Allergan, Inc., Irvine, California 92715.
Neff
J
J
Zolezio
H
H
Sandri
R
R
D000287:Administration, Topical; D000818:Animals; D001381:Azepines / Q000493:pharmacokinetics* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000032:analysis; D006854:Hydrocortisone / Q000493:pharmacokinetics*; D051381:Rats; D012869:Skin Absorption / Q000187:drug effects*; D013997:Time Factors; D014018:Tissue Distribution
D001381:Azepines; C051435:hexahydro-1-lauroyl-1H-azepine; D006854:Hydrocortisone