Impaired metabolism of azathioprine in carbon tetrachloride-injured rats.
The metabolism of 6-(1-methyl-4-nitro-5-imidazolyl) thiopurine (azathioprine) in liver-injured rats was studied in vivo by measuring the clearance rate (K) of the drug from the blood, and its excretion in the urine. The K values in probenecid, diethyl maleate and carbon tetrachloride (CC14)-treated rats were much smaller than those in control rats. Probenecid, a known inhibitor of glutathione S-transferase, inhibited the urine excretion of azathioprine, and diethyl maleate produced a prompt depletion of hepatic reduced glutathione (GSH). Reduced levels of both GSH and glutathione S-transferase activity were observed in rats treated with CC14. Pretreatment with GSH, producing a slight and temporal increase of GSH in liver, resulted in no significant change of the K value. These findings, together with the reported kinetic data of the transferase, indicate that the conversion of azathioprine to 6-mercaptopurine (6-MP) in vivo may be catalyzed largely enzymatically by glutathione S-transferase in the liver.
D000818:Animals; D001379:Azathioprine / Q000378:metabolism*; D002251:Carbon Tetrachloride / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008298:Maleates / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D011339:Probenecid / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D008298:Maleates; D002251:Carbon Tetrachloride; D005982:Glutathione Transferase; C014476:diethyl maleate; D005978:Glutathione; D001379:Azathioprine; D011339:Probenecid