Ratain M J, Mick R, Berezin F, Janisch L, Schilsky R L, Williams S F, Smiddy J
Department of Medicine, University of Chicago Pritzker School of Medicine, IL.
Clin Pharmacol Ther. 1991 Nov;50(5 Pt 1):573-9. doi: 10.1038/clpt.1991.183.
Patients receiving the investigational antineoplastic agent amonafide underwent prospective determination of acetylator phenotype with use of caffeine as a test drug. Fast acetylators of caffeine had significantly greater toxicity (myelosuppression) after amonafide treatment than slow acetylators, presumably because of greater conversion of amonafide to the active acetylated metabolite. Furthermore, the estimated area under the plasma concentration-time curve of amonafide was significantly greater in the fast acetylators, indicating that the total plasma clearance was paradoxically lower in this group. It is hypothesized that this paradox is attributable to competition for oxidation of amonafide by its acetylated metabolite (parallel pathway interaction). Pretreatment white blood count and patient age were also independent predictors of leukopenia. In addition, it was noted that the ratio of actual to ideal body weight was significantly higher in the fast acetylators. Studies are in progress to determine the optimal amonafide dose in both acetylator subgroups.
接受研究性抗肿瘤药物氨苯吖啶治疗的患者，使用咖啡因作为测试药物对乙酰化表型进行了前瞻性测定。氨苯吖啶治疗后，咖啡因快速乙酰化者比慢速乙酰化者有明显更大的毒性（骨髓抑制），这可能是因为氨苯吖啶向活性乙酰化代谢物的转化更多。此外，氨苯吖啶的血浆浓度-时间曲线下面积在快速乙酰化者中显著更大，表明该组的总血浆清除率反常地更低。据推测，这种反常现象归因于氨苯吖啶的乙酰化代谢物对其氧化的竞争（平行途径相互作用）。治疗前白细胞计数和患者年龄也是白细胞减少的独立预测因素。此外，还注意到快速乙酰化者的实际体重与理想体重之比显著更高。目前正在进行研究以确定两个乙酰化亚组中的最佳氨苯吖啶剂量。
