RT Journal Article SR Electronic T1 Induction of Glutathione Synthesis Explains Pharmacodynamics of High-Dose Busulfan in Mice and Highlights Putative Mechanisms of Drug Interaction JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 306 OP 314 DO 10.1124/dmd.106.012880 VO 35 IS 2 A1 Jérôme Bouligand A1 Alain Deroussent A1 Nicolas Simonnard A1 Paule Opolon A1 Jackie Morizet A1 Elisabeth Connault A1 Estelle Daudigeos A1 Micheline Re A1 Angelo Paci A1 Gilles Vassal YR 2007 UL http://dmd.aspetjournals.org/content/35/2/306.abstract AB Busulfan is an example of a drug eliminated through glutathione S-transferase (GST)-catalyzed conjugation with reduced glutathione (GSH). We studied the pharmacokinetics and toxicity of busulfan in C57BL6 mice in correlation with liver GST activity and GSH synthesis by accurate determination of precursors, namely, γ-glutamyl-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 metabolism was correlated with an increase in liver cysteine content and enhanced glutathione synthesis rate, whereas GST activity was unchanged. To our knowledge, this is the first time that in vivo flux of GSH synthesis has been shown to be closely related to a drug plasma clearance and toxicity. These results allow hypothesizing that GSH liver synthesis may directly influence busulfan clearance in humans with possible implications in the occurrence of hepatic veno-occlusive disease. The American Society for Pharmacology and Experimental Therapeutics