Glutathione S-transferase activity influences busulfan pharmacokinetics inpatients with beta thalassemia major undergoing bone marrow transplantation

Busulfan, at a dose of 16 mg/kg, is widely used in combination with cycloph osphamide as a conditioning regimen for patients undergoing bone marrow tra nsplantation. Wide interindividual variation in busulfan kinetics and rapid clearance of the drug have been reported, especially in children. Some of the factors contributing to interpatient variability have been identified. They include circadian rhythms, age, disease, drug interaction, changes in hepatic function, and busulfan bioavailability. In this study, we demonstra te that hepatic glutathione S-transferase (GST) activity correlates negativ ely with busulfan maximum and minimum concentrations (Pearson's correlation r = -0.74 and -0.77, respectively) and positively with busulfan clearance (Pearson's correlation r = 0.728) in children with thalassemia major in the age range of 2 to 15 years. We also found that plasma alpha GST levels wer e 5 to 10 times higher in patients with thalassemia than in normal controls and age-matched leukemic patients, either reflecting extensive liver damag e, elevated expression of the enzyme, or both in thalassemic patients. Plas ma alpha GST concentrations showed a similar correlation with busulfan kine tic parameters to that observed for hepatic GST. The status of hepatic GST activity accounts, at least in part, for the observed interindividual varia tion in busulfan kinetics, while the observed association with plasma alpha GST is difficult to explain at present.