I. Grattagliano et al., Effect of oral and intravenous S,N-diacetylcysteine monoethyl ester on circulating and hepatic sulfhydryls in the rat, J PHARM EXP, 294(1), 2000, pp. 155-159
Citations number
25
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
The role of GSH in the detoxification of reactive metabolites of oxygen and
xenobiotics, in gene expression, and as a source of cysteine is well estab
lished. Because decreased circulating and intracellular concentrations of G
SH might be of pathogenetic relevance in several clinical conditions, there
is a growing interest in pharmacological interventions to correct a derang
ed sulfhydryl status. In this study, the disposition and the effect of S,N-
diacetylcysteine monoethyl ester (DACE) on sulfhydryls were investigated af
ter i.v. and intraduodenal (i.d.) administrations to rats. DACE was rapidly
hydrolyzed and deacetylated to N-acetylcysteine and cysteine in plasma. Hi
gh concentrations of cysteine were attained in the circulation and in the l
iver after i.v. and i.d. administrations of 5 mmol/kg DACE, and physiologic
al levels of GSH in the liver and in plasma increased by 30 and 300%, respe
ctively, with i.v. and i.d. administrations. Incubation of peripheral blood
mononuclear cells with 1 mM DACE resulted in higher intracellular concentr
ations of cysteine and GSH after 24 h than incubations with equimolar conce
ntrations of cysteine, N-acetylcysteine, or oxothiazolidine carboxylic acid
, respectively. It is concluded that DACE provides an efficient delivery sy
stem for cysteine that markedly increases intra- and extracellular cysteine
and GSH after i.v. and i.d. administrations. Because its uptake into cells
is probably not dependent on an active transport process, DACE results in
higher intracellular concentrations of cysteine than those resulting from o
ther prodrugs of cysteine and cysteine itself. The compound may thus have a
dvantages over other compounds for the correction of a deranged sulfhydryl
status.