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Drug Metabolism and Disposition Fast Forward
First published on July 30, 2007; DOI: 10.1124/dmd.107.015727

0090-9556/07/3511-2015-2022$20.00
DMD 35:2015-2022, 2007

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Specificity of Procaine and Ester Hydrolysis by Human, Minipig, and Rat Skin and Liver

Christopher Jewell, Chrisita Ackermann, N. Ann Payne, Gwendolyn Fate, Richard Voorman, and Faith M. Williams

Toxicology Unit, School of Clinical and Laboratory Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom (C.J., F.M.W.); and Pfizer Inc., Ann Arbor, Michigan (C.A., N.A.P., G.F., R.V.)

The capacity of human, minipig, and rat skin and liver subcellular fractions to hydrolyze the anesthetic ester procaine was compared with carboxylesterase substrates 4-methylumbelliferyl-acetate, phenylvalerate, and para-nitrophenylacetate and the arylesterase substrate phenylacetate. Rates of procaine hydrolysis by minipig and human skin microsomal and cytosolic fractions were similar, with rat displaying higher activity. Loperamide inhibited procaine hydrolysis by human skin, suggesting involvement of human carboxylesterase hCE2. The esterase activity and inhibition profiles in the skin were similar for minipig and human, whereas rat had a higher capacity to metabolize esters and a different inhibition profile. Minipig and human liver and skin esterase activity was inhibited principally by paraoxon and bis-nitrophenyl phosphate, classical carboxylesterase inhibitors. Rat skin and liver esterase activity was inhibited additionally by phenylmethylsulfonyl fluoride and the arylesterase inhibitor mercuric chloride, indicating a different esterase profile. These results have highlighted the potential of skin to hydrolyze procaine following topical application, which possibly limits its pharmacological effect. Skin from minipig used as an animal model for assessing transdermal drug preparations had similar capacity to hydrolyze esters to human skin.

Address correspondence to: Prof. Faith M. Williams, Toxicology Unit, School of Clinical and Laboratory Sciences, 4th Floor, Devonshire Bldg., Devonshire Terrace, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4EA, UK. E-mail: f.m.williams{at}ncl.ac.uk






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