Abstract
The relationship between age and busulfan apparent oral clearance (Cl/F) expressed relative to adjusted ideal body weight and body surface area (bsa) was evaluated in 135 children aged 0 to 16 years undergoing hematopoietic stem cell transplantation for various disorders. Busulfan plasma levels were measured by gas chromatography-mass spectrometry after the first daily dose of the 4-day dosing regimen. Cl/F expressed relative to adjusted ideal body weight (ml/min/kg) and bsa (ml/min/m2) was lower in 9- to 16-year-old (y.o.) compared with 0- to 4-y.o. children (49 and 30%; p < .001). We hypothesized that the greater busulfan Cl/F observed in young children was in part due to enhanced (first-pass intestinal) metabolism. Busulfan conjugation rate was compared in incubations with human small intestinal biopsy specimens from healthy young (1- to 3-y.o.) and older (9- to 17-y.o.) children. Villin content in biopsy specimens was determined by Western blot and busulfan conjugation rate was expressed relative to villin content to control for differences in epithelial cell content in pinch biopsies. Intestinal biopsy specimens from young children had a 77% higher busulfan conjugation rate (p = .037) compared with older children. We have previously shown that glutathione-S-transferase (GST) A1–1 is the major isoform involved in busulfan conjugation, and that this enzyme is expressed uniformly along the length of 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 appears to result at least in part from enhanced intestinal GSTA1–1 expression in young children.
Footnotes
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Send reprint requests to: John T. Slattery, Ph.D., Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., D2–100, Seattle, WA 98109-1024. E-mail: jts{at}u.washington.edu
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↵1 This work was supported in part by the National Institutes of Health Grants CA18029 and ES07033.
- Abbreviations used are::
- AUC
- area under the plasma concentration-time curve
- AIBW
- adjusted ideal body weight
- bsa
- body surface area
- BW
- body weight
- Cl/F
- apparent oral clearance
- CSS
- average steady-state concentration
- IBW
- ideal body weight
- GST
- glutathioneS-transferases
- THT+
- γ-glutamyl-β-(S-tetrahydrothiophenium ion) alanyl-glycine
- y.o.
- year(s) old
- IOD
- integrated optical density
- Received June 16, 1999.
- Accepted September 9, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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