Background Busulfan is used in preparative regimens prior to stem cell transplantation (SCT). There is significant inter-patient variability in busulfan pharmacokinetics (PK) and outcome is related to exposure.
To date, only polymorphisms in genes encoding for glutathione-S-transferases have been studied; they could only explain a small portion of the variability in PK.
Purpose To investigate the role of other genetic variants on busulfan clearance by interrogating 1,936 variants in 225 genes that are involved in drug absorption, distribution, metabolism and excretion (ADME).
Materials and Methods 62 adult patients who received busulfan were genotyped using the Drug Metabolizing Enzymes and Transporters (DMET) array. Busulfan clearance was estimated with a limited sampling (t = 2.5, 4 hrs) PK model. Individual SNPs were associated with busulfan clearance. Top SNPs and haplotypes were replicated in an independent cohort (n = 78).
Results In the discovery cohort 7 variants (3 SNPs and 4 haplotypes) explained 64% (adjusted R2) of variance in busulfan clearance (p < 0.001). These genetic variants, located in GSTA5, CYP2C19, CYP39A1 (2 haplotypes), ABCB4, SLC22A4 and SLC7A8, were replicated in the second cohort. One haplotype in GSTA5 (rs4715354 and rs7746993) remained statistically significant (P = 0.025) for correlation with busulfan clearance.
Conclusions This is the first study using an exploratory pharmacogenetic approach in 225 genes involved in ADME to explain the inter-individual variability in busulfan clearance. The GSTA5 haplotype was significantly correlated with busulfan clearance, both in the discovery and replication cohort. No additional genetic markers involved in drug metabolism and transport appear to be associated with busulfan clearance.
No conflict of interest.
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