Induction of Glutathione Synthesis Explains Pharmacodynamics of High-Dose Busulfan in Mice and Highlights Putative Mechanisms of Drug Interaction

Busulfan is an example of a drug eliminated through glutathione S-transferase (GST)-catalyzed conjugation with reduced glutathi-one (GSH). We studied the pharmacokinetics and toxicity of busul-fan in C57BL6 mice in correlation with liver GST activity and GSH synthesis by accurate determination of precursors, namely, -glu-tamyl-cysteine and cysteine. A significantly lower incidence of acute toxicity was observed in mice receiving busulfan 16.5 mg/kg twice a day compared with animals receiving 33 mg/kg once a day. In both cases, a total dose of 132 mg/kg was administered over 4 days. The difference in toxicity was explained by pharmacokinetics since a strong induction of clearance was observed only in animals treated twice daily. Induction of metabolismwas correlated with an increase in liver cysteine content and enhanced glutathione syn-thesis rate, whereas GST activity was unchanged. To our knowl-edge, this is the first time that in vivo flux of GSH synthesis ha