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 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, gamma-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.
Bouligand
Jérôme
J
Unité Propre de Recherche et de l'Enseignement Supérieur, Equipe d'Accueil 3535, Pharmacology and New Treatments of Cancers, IFR54, University Paris XI and Institut Gustave Roussy, Villejuif, France.
Deroussent
Alain
A
Simonnard
Nicolas
N
Opolon
Paule
P
Morizet
Jackie
J
Connault
Elisabeth
E
Daudigeos
Estelle
E
Re
Micheline
M
Paci
Angelo
A
Vassal
Gilles
G
D000818:Animals; D016026:Bone Marrow Transplantation; D002066:Busulfan / Q000493:pharmacokinetics / Q000633:toxicity*; D004347:Drug Interactions; D005978:Glutathione / Q000096:biosynthesis*; D005982:Glutathione Transferase / Q000378:metabolism; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL
D005982:Glutathione Transferase; D002066:Busulfan; D005978:Glutathione