title: Pharmacometabonomic Prediction of Busulfan Clearance in Hematopoetic Cell Transplant Recipients.
abstract: Intravenous (IV) busulfan doses are often personalized to a concentration at steady state (Css) using the patient's clearance, which is estimated with therapeutic drug monitoring. We sought to identify biomarkers of IV busulfan clearance using a targeted pharmacometabonomics approach. A total of 200 metabolites were quantitated in 106 plasma samples, each obtained before IV busulfan administration in hematopoietic cell transplant (HCT) recipients. Both univariate linear regression with false discovery rate (FDR) and pathway enrichment analyses using the Global test were performed. In the univariate analysis, glycine, N-acetylglycine, 2-hydroxyisovaleric acid, creatine, serine, and tyrosine were statistically significantly associated with IV busulfan clearance at P < 0.05, with the first three satisfying the FDR of q < 0.1. Using pathway enrichment analysis, the glycine, serine, and threonine metabolism pathway was statistically significantly associated with IV busulfan clearance at P < 0.05 and q < 0.1, and a pathway impact >0.1. Glycine is a component of glutathione, which is conjugated with busulfan via glutathione transferase enzymes. These results demonstrate the potential utility of pharmacometabonomics to inform IV busulfan dosing. Future studies are required to validate these findings.
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, United States.|University of Washington , Seattle, Washington 98195, United States.
authors.forename: Sandi L
authors.initials: SL
authors.lastname: Navarro
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, United States.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Randolph
authors.affiliation: University of Washington , Seattle, Washington 98195, United States.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Shireman
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, United States.|University of Washington , Seattle, Washington 98195, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Raftery
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109, United States.|University of Washington , Seattle, Washington 98195, United States.
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
mesh_terms: D015415:Biomarkers / Q000097:blood; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016903:Drug Monitoring / Q000379:methods*; D005998:Glycine / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053858:Metabolic Networks and Pathways; D055432:Metabolomics / Q000379:methods*; D066027:Transplant Recipients
chemical_list: D015415:Biomarkers; D002066:Busulfan; D005998:Glycine
keywords: busulfan; hematopoietic cell transplant; metabolomics; pharmacokinetics; pharmacometabonomics