Age-dependent tetrahydrothiophenium ion formation in young children and adults receiving high-dose busulfan.
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))(0-->6)] 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))(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 = 0.0098) 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))(0-->6) is an enhanced ability of children to metabolize busulfan through glutathione conjugation.
Gibbs
J P
JP
Department of Pharmaceutics, University of Washington, Seattle 98195, USA.
Murray
G
G
Risler
L
L
Chien
J Y
JY
Dev
R
R
Slattery
J T
JT
D000042:Absorption; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000375:Aging / Q000097:blood / Q000378:metabolism*; D018906:Antineoplastic Agents, Alkylating / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002066:Busulfan / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D005978:Glutathione / Q000097:blood / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007223:Infant; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D013876:Thiophenes / Q000097:blood / Q000493:pharmacokinetics*
D018906:Antineoplastic Agents, Alkylating; D013876:Thiophenes; D005982:Glutathione Transferase; D002066:Busulfan; D005978:Glutathione