Specificity of procaine and ester hydrolysis by human, minipig, and rat skin and liver

被引:43
作者
Jewell, Christopher
Ackermann, Chrisita
Payne, N. Ann
Fate, Gwendolyn
Voorman, Richard
Williams, Faith M.
机构
[1] Newcastle Univ, Sch Clin & Lab Sci, Toxicol Unit, Newcastle Upon Tyne NE2 4EA, Tyne & Wear, England
[2] Pfizer Inc, Ann Arbor, MI USA
关键词
D O I
10.1124/dmd.107.015727
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:2015 / 2022
页数:8
相关论文
共 28 条
[1]   Human keratinocyte cultures as models of cutaneous esterase activity [J].
Barker, CL ;
Clothier, RH .
TOXICOLOGY IN VITRO, 1997, 11 (05) :637-640
[2]   FATE OF FLUAZIFOP BUTYL IN RAT AND HUMAN SKIN INVITRO [J].
CLARK, NWE ;
SCOTT, RC ;
BLAIN, PG ;
WILLIAMS, FM .
ARCHIVES OF TOXICOLOGY, 1993, 67 (01) :44-48
[3]   Purification and molecular cloning of porcine intestinal glycerol-ester hydrolase - Evidence for its identity with carboxylesterase [J].
David, L ;
Guo, XJ ;
Villard, C ;
Moulin, A ;
Puigserver, A .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1998, 257 (01) :142-148
[4]  
Hewitt PG, 2000, DRUG METAB DISPOS, V28, P755
[5]  
HOTCHKISS SAM, 1992, PROGR DRUG METABOLIS, V13, P217
[6]   Structure-activity relationships for substrates and inhibitors of mammalian liver microsomal carboxylesterases [J].
Huang, TL ;
Shiotsuki, T ;
Uematsu, T ;
Borhan, B ;
Li, QX ;
Hammock, BD .
PHARMACEUTICAL RESEARCH, 1996, 13 (10) :1495-1500
[7]   Evidence for the involvement of a pulmonary first-pass effect via carboxylesterase in the disposition of a propranolol ester derivative after intravenous administration [J].
Imai, T ;
Yoshigae, Y ;
Hosokawa, M ;
Chiba, K ;
Otagiri, M .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2003, 307 (03) :1234-1242
[8]   Substrate specificity of carboxylesterase isozymes and their contribution to hydrolase activity in human liver and small intestine [J].
Imai, Teruko ;
Taketani, Megumi ;
Shii, Mayumi ;
Hosokawa, Masakiyo ;
Chiba, Kan .
DRUG METABOLISM AND DISPOSITION, 2006, 34 (10) :1734-1741
[9]   Enzymes involved in the bioconversion of ester-based prodrugs [J].
Liederer, Bianca M. ;
Borchardt, Ronald T. .
JOURNAL OF PHARMACEUTICAL SCIENCES, 2006, 95 (06) :1177-1195
[10]   Pharmacogenomic assessment of carboxylesterases 1 and 2 [J].
Marsh, S ;
Xiao, M ;
Yu, JS ;
Ahluwalia, R ;
Minton, M ;
Freimuth, RR ;
Kwok, PY ;
McLeod, HL .
GENOMICS, 2004, 84 (04) :661-668