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Up-regulation of glutathione S-transferase activity in enterocytes of young children
J P Gibbs1, C A Liacouras, R N Baldassano
1Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024,USA.
Insights
Young children show higher busulfan clearance due to increased intestinal metabolism. This enhanced first-pass metabolism is linked to greater glutathione-S-transferase A1-1 expression in their intestines.
Area of Science:
- Pharmacokinetics
- Pediatric Oncology
- Drug Metabolism
Background:
- Busulfan is a key chemotherapeutic agent used in hematopoietic stem cell transplantation.
- Apparent oral clearance (Cl/F) of busulfan varies significantly with age in pediatric patients.
- Understanding age-related differences in busulfan pharmacokinetics is crucial for optimizing dosing and improving patient outcomes.
Purpose of the Study:
- To investigate the relationship between age and busulfan apparent oral clearance (Cl/F) in children.
- To explore the role of intestinal first-pass metabolism in age-dependent busulfan Cl/F.
- To compare busulfan conjugation rates in intestinal tissues of young versus older children.
Main Methods:
- Evaluated busulfan Cl/F relative to adjusted ideal body weight and body surface area in 135 children (0-16 years).
- Measured busulfan plasma levels using gas chromatography-mass spectrometry.
- Assessed busulfan conjugation rate in human small intestinal biopsy specimens from healthy children (1-3 years vs. 9-17 years), controlling for villin content.
Main Results:
- Busulfan Cl/F was significantly lower in older children (9-16 years) compared to younger children (0-4 years).
- Intestinal biopsy specimens from young children exhibited a 77% higher busulfan conjugation rate compared to older children.
- Enhanced busulfan conjugation in young children is attributed to increased expression of glutathione-S-transferase (GST) A1-1.
Conclusions:
- Age-dependent busulfan Cl/F in children is significantly influenced by enhanced intestinal metabolism.
- Increased expression of GSTA1-1 in the small intestine of young children contributes to higher busulfan clearance.
- These findings highlight the importance of age-specific pharmacokinetic considerations for busulfan therapy in pediatric patients.
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/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 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.