DISPOSITION OF GLUTATHIONE MONOETHYL ESTER IN THE RAT - GLUTATHIONE ESTER IS A SLOW-RELEASE FORM OF EXTRACELLULAR GLUTATHIONE

Glutathione monethyl ester (GSHE) is thought to deliver glutathione (G SH) directly and intact into cell cytosol and therefore might have the rapeutic potential in states of GSH deficiency. To better understand t he disposition of GSHE, the pharmacokinetics of GSHE and GSH were comp ared in rats. Fifteen min after an i.v. dose of 5 mmol/kg GSHE, the pl asma concentration of GSHE was 7.2 +/- 1.2 mmol/l and the plasma conce ntration of GSH had increased from 0.009 +/- 0.002 to 2.5 +/- 0.3 mmol /l. The areas under the plasma concentration time curves of GSH were i dentical after either the administration of GSHE or GSH, but the mean residence time of GSH in plasma was significantly longer after GSHE. T he concentration of GSHE in liver reached a peak of 0.66 +/- 0.09 mu m ol/g. Intrahepatic concentrations of cysteine and GSH increased from 5 3 +/- 15 to 319 +/- 41 nmol/g and from 5.5 +/- 0.4 to 7.8 +/- 1.5 mu m ol/g, respectively, and remained elevated for 2 hr. Similar increases occurred after administration of GSH. However, the concentrations of c ysteine and GSH peaked earlier and had returned to baseline by 2 hr. Q ualitatively similar results were obtained in rats pretreated with L-b uthionine-[S, R]-sulfoximine that partially inhibits GSH synthesis. GS HE added to rat plasma at a concentration of 10 mM was hydrolyzed to G SH at a rate of 0.1 mu mol/min. Our data indicate that GSHE is not rea dily taken up by the liver, but is hydrolyzed by esterases in plasma a nd thereby gradually releases GSH in the extracellular space. It thus acts as a slow release form of GSH that is then further metabolized by gamma-glutamyltransferase, thereby providing the precursor amino acid s for de novo synthesis of GSH. Because of this slow release, there is a more sustained increase in intracellular cysteine and subsequently GSH than after the administration of unmodified GSH.