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First published on November 28, 2006; DOI: 10.1124/dmd.106.012880

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Received for publication September 12, 2006.
Revised November 16, 2006.
Accepted for publication November 17, 2006.

Induction of glutathione synthesis explains pharmacodynamics of high-dose busulfan in mice and highlights putative mechanisms of drug interaction

Jerome BOULIGAND 1, Alain DEROUSSENT 2, Nicolas SIMONNARD 1, Paule OPOLON 3, Jackie MORIZET 1, Elisabeth CONNAULT 3, Estelle DAUDIGEOS 1, Micheline RE 1, Angelo PACI 1, Gilles VASSAL 1*

1 UPRES EA3535 - Institut Gustave Roussy 2 IFR54 - Institut Gustave Roussy 3 UMR8121 - Institut Gustave Roussy

* Address correspondence to: E-mail: gilles.vassal{at}igr.fr

Abstract

Busulfan is an example of a drug eliminated through glutathione S-transferase (GST)-catalyzed conjugation with 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 significant lower incidence of acute toxicity was observed in mice receiving busulfan 16.5 mg/kg twice a day as compared to 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 of 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, while GST activity was unchanged. To our knowledge, this is the first time that in vivo flux of GSH synthesis is 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.


Key words: anticancer agents, drug clearance, glutathione, glutathione metabolism, glutathione transferases, hematotoxicity, hepatotoxicity, induction, metabolite kinetics, pharmacokinetics


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