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Age-dependent Tetrahydrothiophenium Ion Formation in Young Children and Adults Receiving High-Dose Busulfan¹

Department of Pharmaceutics, University of Washington, Seattle, Washington 98195 [J. P. G., J. Y. C., R. D., J. T. S.], and Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 [G. M., L. R., J. T. S.]

Busulfan, a bifunctional alkylating agent, is a mainstay of myeloablative preparative regimens before hematopoietic stem cell transplantation. The apparent oral clearance of busulfan expressed relative to body surface area is 2–3-fold higher in children 1–4 years old than it is in adults. The first step in busulfan elimination is the formation of a tetrahydrothiophenium ion (THT⁺) in a glutathione S-transferase-catalyzed reaction. We present computer simulations that demonstrate that the ratio of the AUC of THT⁺ to that of busulfan over 6 h [(AUC_THT⁺/AUC_BU)₀₆] is highly correlated (r² = 0.805) with the determinants of THT⁺ formation and is virtually independent of the determinants of its elimination (r² = 0.0201). We compared (AUC_THT⁺/AUC_BU)₀₆ determined in 14 children (0.5–4 years) to that of 11 adults (12–54 years) and found a 1.5-fold elevation in the area ratio (P = 0.0098) and a similarly significant increase in busulfan apparent oral clearance expressed relative to body surface area (P = 0.042). The only common explanation for the elevated busulfan apparent oral clearance and (AUC_THT⁺/AUC_BU)₀₆ is an enhanced ability of children to metabolize busulfan through glutathione conjugation.

¹ Supported in part by NIH Grants CA18029 and GM07750.

² To whom requests for reprints should be addressed, at Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, AB 122, P. O. Box 19024, Seattle, WA 98109-1024. Phone: (206) 667-3372; Fax: (206) 667-6115; E-mail: jts@u.washington.edu.

Received 4/ 7/97. Accepted 10/15/97.

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