Re‐visiting Busulfan Disposition: Significance and Clearance Mechanisms

Abstract

Busulfan (Bu) is a chemotherapeutic with narrow therapeutic range and extensive inter‐individual pharmacokinetic (PK) variability. Bu disposition occurs in part by glutathionylation, but newer pharmacogenomic studies point towards, but not proven, other important metabolism pathways. The objectives of this study were to determine the dangers of impaired Bu metabolism in hematopoietic stem cell transplantation patients, and to explore alternative routes of Bu clearance in vitro. In a retrospective analysis of MDACC patients (n=752), the mean Bu clearance was 101 mL/min/m2 that ranged from 52‐150. Among these patients, about 20% had a low Bu clearance 蠄 80. There was a statistically significant correlation between low Bu clearance and poor survival (p<0.01). Furthermore, low Bu clearance was associated with a greater risk of liver toxicity (p=0.0021) and graft‐vs‐host disease(p=0.0014). Bu stimulated P‐gp ATPase activity only at high conc (100 µM), with a 3.6‐fold increase over basal activity. Therefore, it is unlikely that P‐gp will affect the PK of Bu in clinical practice. A LC‐MS/MS assay (LLOQ=0.2µM) was developed to measure the extent of Bu depletion in HLM. Compared to control, the %Bu remaining at 2 hr was 77% and 74% for Bu 3 µM and 90 μM, respectively. No significant depletion of Bu was observed in HLM pre‐treated with CYP inhibitor 1‐ABT. We have shown that CYP enzymes likely have a role in Bu metabolism, and are a focal point for further studying the troubling cross‐patient variabilities in Bu PK, treatment efficacy and toxicity.