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Modulation of hepatic glutathione levels by acetaninophen
263
Pharmacological Research, W. 26, Supplement I, 1992 INHIBITION OF FLURBI PROFEN.
ORNITHINE-DECARBOXYLASE
IN
RATS
PRODUCED
BY
S(+)
Francesco Michele Runcl, Maria Raffaella Romeo, Giorgio Segre*, Giancarlo Drunl Institute of Pharmacology, School of Medicine, *and Laboratory of Pharmacoklnetics, University of Siena. The two enantiomeric forms of flurbiprofen possess different activity as antinflammatory drugs likewise all of the 2 arylpropionic acids non steroidal antiinflammatory agents (1). These differences were assayed by evaluating the effect of Rand S forms of flurbiprofen on the release of 14C02 after administration to rats of ’4C-labeled ornithlne. The 14C02 eliminated by rats, was evaluated after 1,2,3 and 6 hours by placing them into a metabolic cage (Metabowl-Jencons) flushed continuously with air.The 1’+02 collected on 5ml of CarboSorb (Packard), was evaluated by a beta-counter (Packard Tri-Cart, 3OOC)(2). Only SC+) flurbiprofen inhibits the 1%02 release by ornithine decarboxylase. Furthermore we carried out the carrageenin induced paw oedema test (3) that showed S(+) to be an effective antagonist of the oedema, at difference of R(-) possessing much lower effectiveness, this probably due to chiral inverston into the SC+)form (I ). References: ( 1)- Urian W Gerry and Fakhreddin Jamali I J. of Pharmac. Science, 7t3,0, 632,1909 (2)-Bruni G., Runci FM, Fiaschi A.I., Segre G. Pharmacol. Research,22,2,97,1990. (3)- Winter CA, Risley EA, Nuss GW. Proc.Soc.Exp.Diol.Med. I I 11 544,1942.
UOUULBTIOU Anna
Ida
OF HEPATIC SLUTLTHIOUE LEVELS BY RCETlHIUOPHEU Lucia tlicheli, Uaniela Cerretani, Maria Romeo, Giorgio Giorgi. of Pharmacology, University of Siena, Italy. Fiaschi,
Raffaella
Institute
(&P&P) is a widely used non prescription produces hepatotoxicity and death in animals after ingestion of high dosages. Toxicity is thought to be produced by N-acetyl-p-benzoquinoneimine, a reactive electrophilic metabolite which reacts with the nucleophilic sulfhydryl group of glutathione (GSH). High dosages of APAP deplete hepatic and suppress the GSH biosynthesis of GSH and therefore the reactive metabolite binds to other nucleophilic macromolecules. In the present study we evaluated in rat liver the kinetic of APRP (3 g/kg OS) which present the Coax at 8th hour (176 us/g tissue). Moreover we have studied the effect of three substances L-2-oxothiazolidine-4-carboxylate (OTZ; 200 mg/kg i-p.) N-acetyl-L-cysteine (NAC; 200 i-p-) and w/kg glutathione (GSH; 2 g/kg i-p.) on the decrease of GSH hepatic levels induced by RPAP (3 glkg OS) in albino Wistar rats. The Acetaminophen
that analgesic and in humans
results
show that by
decreased
levels,
do
not
APAP
OTZ
is
whereas counteract
able NAC
fully
to
normalize
and GSH, even A P A P effect.
glutathione levels if increase such
Pharmacological Research, W. 26, Supplement I, 1992 INHIBITION OF FLURBI PROFEN.
ORNITHINE-DECARBOXYLASE
IN
RATS
PRODUCED
BY
S(+)
Francesco Michele Runcl, Maria Raffaella Romeo, Giorgio Segre*, Giancarlo Drunl Institute of Pharmacology, School of Medicine, *and Laboratory of Pharmacoklnetics, University of Siena. The two enantiomeric forms of flurbiprofen possess different activity as antinflammatory drugs likewise all of the 2 arylpropionic acids non steroidal antiinflammatory agents (1). These differences were assayed by evaluating the effect of Rand S forms of flurbiprofen on the release of 14C02 after administration to rats of ’4C-labeled ornithlne. The 14C02 eliminated by rats, was evaluated after 1,2,3 and 6 hours by placing them into a metabolic cage (Metabowl-Jencons) flushed continuously with air.The 1’+02 collected on 5ml of CarboSorb (Packard), was evaluated by a beta-counter (Packard Tri-Cart, 3OOC)(2). Only SC+) flurbiprofen inhibits the 1%02 release by ornithine decarboxylase. Furthermore we carried out the carrageenin induced paw oedema test (3) that showed S(+) to be an effective antagonist of the oedema, at difference of R(-) possessing much lower effectiveness, this probably due to chiral inverston into the SC+)form (I ). References: ( 1)- Urian W Gerry and Fakhreddin Jamali I J. of Pharmac. Science, 7t3,0, 632,1909 (2)-Bruni G., Runci FM, Fiaschi A.I., Segre G. Pharmacol. Research,22,2,97,1990. (3)- Winter CA, Risley EA, Nuss GW. Proc.Soc.Exp.Diol.Med. I I 11 544,1942.
UOUULBTIOU Anna
Ida
OF HEPATIC SLUTLTHIOUE LEVELS BY RCETlHIUOPHEU Lucia tlicheli, Uaniela Cerretani, Maria Romeo, Giorgio Giorgi. of Pharmacology, University of Siena, Italy. Fiaschi,
Raffaella
Institute
(&P&P) is a widely used non prescription produces hepatotoxicity and death in animals after ingestion of high dosages. Toxicity is thought to be produced by N-acetyl-p-benzoquinoneimine, a reactive electrophilic metabolite which reacts with the nucleophilic sulfhydryl group of glutathione (GSH). High dosages of APAP deplete hepatic and suppress the GSH biosynthesis of GSH and therefore the reactive metabolite binds to other nucleophilic macromolecules. In the present study we evaluated in rat liver the kinetic of APRP (3 g/kg OS) which present the Coax at 8th hour (176 us/g tissue). Moreover we have studied the effect of three substances L-2-oxothiazolidine-4-carboxylate (OTZ; 200 mg/kg i-p.) N-acetyl-L-cysteine (NAC; 200 i-p-) and w/kg glutathione (GSH; 2 g/kg i-p.) on the decrease of GSH hepatic levels induced by RPAP (3 glkg OS) in albino Wistar rats. The Acetaminophen
that analgesic and in humans
results
show that by
decreased
levels,
do
not
APAP
OTZ
is
whereas counteract
able NAC
fully
to
normalize
and GSH, even A P A P effect.
glutathione levels if increase such