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

B. Poonkuzhali, M. Chandy, A. Srivastava, D. Dennison, R. Krishnamoorthy

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Abstract

Busulfan, at a dose of 16 mg/kg, is widely used in combination with cyclophosphamide as a conditioning regimen for patients undergoing bone marrow transplantation. 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 demonstrate that hepatic glutathione S-transferase (GST) activity correlates negatively 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 were 5 to 10 times higher in patients with thalassemia than in normal controls and age-matched leukemic patients, either reflecting extensive liver damage, elevated expression of the enzyme, or both in thalassemic patients. Plasma alpha GST concentrations showed a similar correlation with busulfan kinetic parameters to that observed for hepatic GST. The status of hepatic GST activity accounts, at least in part, for the observed interindividual variation in busulfan kinetics, while the observed association with plasma alpha GST is difficult to explain at present.

Original languageEnglish
Pages (from-to)264-267
Number of pages4
JournalDrug Metabolism and Disposition
Volume29
Issue number3
Publication statusPublished - 2001

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Busulfan
beta-Thalassemia
Glutathione Transferase
Bone Marrow Transplantation
Pharmacokinetics
Liver
Thalassemia
Circadian Rhythm
Drug Interactions
Cyclophosphamide
Biological Availability
Enzymes
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Glutathione S-transferase activity influences busulfan pharmacokinetics in patients with beta thalassemia major undergoing bone marrow transplantation. / Poonkuzhali, B.; Chandy, M.; Srivastava, A.; Dennison, D.; Krishnamoorthy, R.

In: Drug Metabolism and Disposition, Vol. 29, No. 3, 2001, p. 264-267.

Research output: Contribution to journalArticle

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AU - Krishnamoorthy, R.

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