Comparison of skin esterase activities from different species.
OBJECTIVE
Many topically applied drugs contain esters that are hydrolyzed in the skin. Minipigs have emerged as potential models of human dermatology and, in some aspects, may be superior to commonly used rat skin. The aims of this study were to evaluate the suitability of minipig and rat skin as in vitro models of human epidermal esterase activity.


METHODS
Naphthyl acetate and para-nitrophenyl acetate were tested as prototypical substrates of carboxylesterases from skin, plasma, and liver. Reaction products were monitored by high-performance liquid chromatography/ultraviolet analysis.


RESULTS
Hydrolysis efficiency in skin was higher than plasma, but lower than liver. The esterase efficiency of rat skin microsomes (580-1100 min(-1) mg(-1)) was two to three orders of magnitude higher than human (1.3-4.2 min(-1) mg(-1)) and minipig microsomes (1.2-4.2 min(-1) mg(-1)). Rat skin cytosol (80-100 min(-1) mg(-1)) was 2- to 10-fold more efficient than human (2.4-67 min(-1) mg(-1)) or minipig cytosol (18-61 min(-1) mg(-1)). Most importantly, human skin fractions displayed kinetics of hydrolysis very similar to minipig skin.


CONCLUSIONS
These studies show minipig skin as an appropriate, potentially valuable model for human epidermal ester metabolism and support the use of minipig skin in preclinical development of topically applied compounds.
Prusakiewicz
Jeffery J
JJ
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, 2800 Plymouth Rd., Ann Arbor, Michigan 48105, USA. Jeff.Prusakiewicz@pfizer.com
Ackermann
Chrisita
C
Voorman
Richard
R
D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001769:Blood / Q000187:drug effects; D043182:Carboxylesterase / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009284:Naphthols / Q000378:metabolism; D009388:Neostigmine / Q000494:pharmacology; D009596:Nitrophenols / Q000378:metabolism / Q000494:pharmacology; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects / Q000201:enzymology*; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature
D002800:Cholinesterase Inhibitors; D009284:Naphthols; D009596:Nitrophenols; C005366:naphthyl acetate; D009388:Neostigmine; C002887:bis(4-nitrophenyl)phosphate; C008642:4-nitrophenyl acetate; D043182:Carboxylesterase; D000110:Acetylcholinesterase