AGE-DEPENDENT TETRAHYDROTHIOPHENIUM ION FORMATION IN YOUNG-CHILDREN AND ADULTS RECEIVING HIGH-DOSE BUSULFAN

Busulfan, a bifunctional alkylating agent, is a mainstay of myeloablat ive preparative regimens before hematopoietic stem cell transplantatio n, 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 i n adults, The first step in busulfan elimination is the formation of a tetrahydrothiophenium ion (THT+) in a glutathione S-transferase-catal yzed reaction, We present computer simulations that demonstrate that t he ratio of the AUC of THT+ to that of busulfan over 6 h [(AUC(THT)+/A UC(BU))(0-->6)] is highly correlated (r(2) = 0.805) with the determina nts of THT+ formation and is virtually independent of the determinants of its elimination (r(2) = 0.0201), We compared (AUC(THT+)/AUC(BU))(0 -->6) 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 = 0.009 8) and a similarly significant increase in busulfan apparent oral clea rance expressed relative to body surface area (P = 0.042), The only co mmon explanation for the elevated busulfan apparent oral clearance and (AUC(THT+)/AUC(BU))(0-->6) is an enhanced ability of children to meta bolize busulfan through glutathione conjugation.