Up-regulation of glutathione S-transferase activity in enterocytes of young children

The relationship between age and busulfan apparent oral clearance (Cl/F) ex pressed relative to adjusted ideal body weight and body surface area (bsa) was evaluated in 135 children aged 0 to 16 years undergoing hematopoietic s tem cell transplantation for various disorders. Busulfan plasma levels were measured by gas chromatography-mass spectrometry after the first daily dos e of the 4-day dosing regimen. Cl/F expressed relative to adjusted ideal bo dy weight (ml/min/kg) and bsa (ml/min/m(2)) was lower in 9- to 16-year-old (y.o.) compared with 0- to 4-y.o. children (49 and 30%; p < .001). We hypot hesized that the greater busulfan Cl/F observed in young children was in pa rt due to enhanced (first-pass intestinal) metabolism. Busulfan conjugation rate was compared in incubations with human small intestinal biopsy specim ens from healthy young (1- to 3-y.o.) and older (9- to 17-y.o.) children. V illin content in biopsy specimens was determined by Western blot and busulf an conjugation rate was expressed relative to villin content to control for differences in epithelial cell content in pinch biopsies. Intestinal biops y specimens from young children had a 77% higher busulfan conjugation rate (p = .037) compared with older children. We have previously shown that glut athione-S-transferase (GST) A1-1 is the major isoform involved in busulfan conjugation, and that this enzyme is expressed uniformly along the length o f adult small intestine. Thus, the greater busulfan conjugation activity in intestinal biopsies of the young children was most likely due to enhanced GSTA1-1 expression. We conclude that age dependence in busulfan Cl/F appear s to result at least in part from enhanced intestinal GSTA1-1 expression in young children.