Bremer Sara, Fløisand Yngvar, Brinch Lorentz, Gedde-Dahl Tobias, Bergan Stein
Departments of *Medical Biochemistry, †Hematology, and ‡Pharmacology, Oslo University Hospital, Rikshospitalet; and §School of Pharmacy, University of Oslo, Norway.
Ther Drug Monit. 2015 Aug;37(4):493-500. doi: 10.1097/FTD.0000000000000180.
Busulfan (Bu) and cyclophosphamide (Cy) are frequently included in conditioning regimens before hematopoietic stem cell transplantation (HSCT). Both drugs are detoxified by glutathione transferases (GST), and GST gene variants may explain some of the interindividual variability in pharmacokinetics and drug toxicity.
The study investigated adult patients (n = 114) receiving oral Bu pre-HSCT. Bu doses were adjusted to obtain an average steady-state concentration (Css) of 900 mcg/L.
Median first dose Bu Css was 1000 mcg/L (600-1780 mcg/L). Patients carrying 1 and 2 GSTA1*B (rs3957357) alleles demonstrated median 12% and 16% higher Bu Css (P ≤ 0.05). Bu exposure (average Css; odds ratio = 1.009, 95% confidence interval = 1.002-1.017, P = 0.013) and GSTM1 gene copy number (odds ratio = 17.1, 95% confidence interval = 1.46-201, P = 0.024) were significant predictors of mortality ≤30 days. The mortality was 25% versus 2% among carriers of 2 versus no GSTM1 copies (P = 0.021). Mortality ≤3 months was associated with higher first dose Bu exposure (1090 versus 980 mcg/L, P = 0.021). GSTM1 expression and high Bu exposure may increase Cy toxicity by reducing intracellular glutathione.
GST genotyping before HSCT may allow better prediction of Bu pharmacokinetics and drug toxicity, and thereby improve outcome after BuCy conditioning.
白消安（Bu）和环磷酰胺（Cy）常用于造血干细胞移植（HSCT）前的预处理方案。这两种药物均通过谷胱甘肽转移酶（GST）进行解毒，而GST基因变异可能解释了药代动力学和药物毒性方面的个体间差异。
该研究调查了114例在HSCT前接受口服Bu的成年患者。调整Bu剂量以获得900 mcg/L的平均稳态浓度（Css）。
首次剂量Bu的Css中位数为1000 mcg/L（600 - 1780 mcg/L）。携带1个和2个GSTA1*B（rs3957357）等位基因的患者，其Bu Css中位数分别高出12%和16%（P≤0.05）。Bu暴露量（平均Css；优势比 = 1.009，95%置信区间 = 1.002 - 1.017，P = 0.013）和GSTM1基因拷贝数（优势比 = 17.1，95%置信区间 = 1.46 - 201，P = 0.024）是30天内死亡率的显著预测因素。携带2个与无GSTM1拷贝的患者，死亡率分别为25%和2%（P = 0.021）。3个月内的死亡率与首次剂量Bu暴露量较高有关（1090对980 mcg/L，P = 0.021）。GSTM1表达和高Bu暴露可能通过降低细胞内谷胱甘肽而增加Cy毒性。
HSCT前进行GST基因分型可能有助于更好地预测Bu的药代动力学和药物毒性，从而改善BuCy预处理后的治疗效果。
