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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.