Specificity of procaine and ester hydrolysis by human, minipig, and rat skin and liver.
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.
Toxicology Unit, School of Clinical and Laboratory Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Christopher
C
Jewell
Chrisita
C
Ackermann
N Ann
NA
Payne
Gwendolyn
G
Fate
Richard
R
Voorman
Faith M
FM
Williams
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004950:Esterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004952:Esters; D005260:Female; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D008099:Liver / Q000201:enzymology*; D008139:Loperamide / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015394:Molecular Structure; D009596:Nitrophenols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010261:Paraoxon / Q000494:pharmacology; D010421:Pentanoic Acids / Q000737:chemistry / Q000378:metabolism; D010648:Phenylacetates / Q000737:chemistry / Q000378:metabolism; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D011343:Procaine / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000201:enzymology*; D013552:Swine; D013556:Swine, Miniature; D014468:Umbelliferones / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D004952:Esters; D009596:Nitrophenols; D010421:Pentanoic Acids; D010648:Phenylacetates; D014468:Umbelliferones; C032078:4-methylumbelliferyl acetate; D011343:Procaine; D010664:Phenylmethylsulfonyl Fluoride; C002887:bis(4-nitrophenyl)phosphate; D008139:Loperamide; C008642:4-nitrophenyl acetate; D004950:Esterases; C025136:phenylacetic acid; D010261:Paraoxon; C400347:5-phenylvaleric acid