BACKGROUND: Busulfan is used in preparative regimens before stem cell transplantation. There is significant interpatient variability in busulfan pharmacokinetics (PK) and exposure is related to outcome. Polymorphisms in genes encoding glutathione-S-transferases have been associated with busulfan PK but only explain a limited portion of the observed variability. AIM: The aim of this study is to identify additional genetic variants associated with busulfan PK by interrogating 1936 variants in 225 genes involved in drug absorption, distribution, metabolism, and excretion (ADME). MATERIALS AND METHODS: In an exploratory cohort (n=65), patients who received busulfan were genotyped with the DMET array. Top SNPs and haplotypes associated with busulfan clearance were validated in an independent validation cohort (n=78). RESULTS: In the exploratory cohort, seven variants were identified to be associated with busulfan clearance (P<0.001). In the validation cohort, only GSTA5 (rs4715354 and rs7746993) remained significantly associated with busulfan clearance (P=0.025). CONCLUSION: This is the first study using an exploratory pharmacogenetic approach to explain the interindividual variability in busulfan PK. The role of glutathione-S-transferases was confirmed, but no additional genetic markers involved in drug ADME appear to be associated with busulfan PK.
BACKGROUND:Busulfan is used in preparative regimens before stem cell transplantation. There is significant interpatient variability in busulfan pharmacokinetics (PK) and exposure is related to outcome. Polymorphisms in genes encoding glutathione-S-transferases have been associated with busulfan PK but only explain a limited portion of the observed variability. AIM: The aim of this study is to identify additional genetic variants associated with busulfan PK by interrogating 1936 variants in 225 genes involved in drug absorption, distribution, metabolism, and excretion (ADME). MATERIALS AND METHODS: In an exploratory cohort (n=65), patients who received busulfan were genotyped with the DMET array. Top SNPs and haplotypes associated with busulfan clearance were validated in an independent validation cohort (n=78). RESULTS: In the exploratory cohort, seven variants were identified to be associated with busulfan clearance (P<0.001). In the validation cohort, only GSTA5 (rs4715354 and rs7746993) remained significantly associated with busulfan clearance (P=0.025). CONCLUSION: This is the first study using an exploratory pharmacogenetic approach to explain the interindividual variability in busulfan PK. The role of glutathione-S-transferases was confirmed, but no additional genetic markers involved in drug ADME appear to be associated with busulfan PK.
Authors: Alan L Myers; Jitesh D Kawedia; Richard E Champlin; Mark A Kramer; Yago Nieto; Romi Ghose; Borje S Andersson Journal: Expert Opin Drug Metab Toxicol Date: 2017-08-17 Impact factor: 4.481
Authors: Mariamena Arbitrio; Maria Teresa Di Martino; Francesca Scionti; Giuseppe Agapito; Pietro Hiram Guzzi; Mario Cannataro; Pierfrancesco Tassone; Pierosandro Tagliaferri Journal: Oncotarget Date: 2016-08-16
Authors: Marc Ansari; Patricia Huezo-Diaz Curtis; Chakradhara Rao S Uppugunduri; Mohammed Aziz Rezgui; Tiago Nava; Vid Mlakar; Laurence Lesne; Yves Théoret; Yves Chalandon; Lee L Dupuis; Tao Schechter; Imke H Bartelink; Jaap J Boelens; Robbert Bredius; Jean-Hugues Dalle; Saba Azarnoush; Petr Sedlacek; Victor Lewis; Martin Champagne; Christina Peters; Henrique Bittencourt; Maja Krajinovic Journal: Oncotarget Date: 2017-08-27
Authors: Veronique Michaud; My Tran; Benoit Pronovost; Philippe Bouchard; Sarah Bilodeau; Karine Alain; Barbara Vadnais; Martin Franco; François Bélanger; Jacques Turgeon Journal: Pharmaceutics Date: 2019-09-01 Impact factor: 6.321