Inhibition of hepatic metabolism of azathioprine in vivo.

Glutathione-mediated thiolysis of azathioprine in the liver is believed to be the main mechanism for the conversion of this drug to 6-mercaptopurine. This metabolic step was inhibited in vivo by pretreating rats with probenecid as indicated both by less hepatic glutathione depletion and by a greater proportion of unmetabolized azathioprine in the liver. Less hepatic gluthathione depletion was also found in the hyperbilirubinemic Gunn rat. These findings indicate that the conversion of azathioprine to 6-mercaptopurine in vovo is mediated enzymatically by the glutathione S-transferases.