Xie Hanjing, Griskevicius Laimonas, Ståhle Lars, Hassan Zuzana, Yasar Umit, Rane Anders, Broberg Ulrika, Kimby Eva, Hassan Moustapha
Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, SE 141-86 Stockholm, Sweden.
Eur J Pharm Sci. 2006 Jan;27(1):54-61. doi: 10.1016/j.ejps.2005.08.008. Epub 2005 Sep 23.
A high degree of interindividual variation in cyclophosphamide (CPA) pharmacokinetics was reported in certain cancer patient groups. To better understand the mechanisms underlying the variation in CPA metabolism, we have investigated the pharmacokinetics of CPA and its active metabolite 4-hydroxycyclophosphamide (4-OH-CPA) in patients with hematological tumors. The pharmacokinetics of CPA and its active metabolite were related to the genotype of CYP2B6, CYP2C9 and CYP2C19. The influence of liver function on CPA metabolism was also evaluated.
Twenty-nine patients with hematological malignancies (MM, ALL or NHL) treated with a conventional CPA dose (1g/m(2)) were recruited to this study. Blood samples were collected before, during and after CPA treatment. HPLC was used to measure plasma concentrations of CPA and 4-OH-CPA. Patients were genotyped for the CYP2B6 G516T, CYP2C92, CYP2C93, CYP2C192 and CYP2C193 alleles. Serum bilirubin levels were measured before the treatment. Data was analyzed individually and by population pharmacokinetic methods, using non-linear mixed effect modeling.
The interindividual variability in exposure to CPA, 4-OHCPA and 4-OH-CPA/CPA was 5.8-, 3.3- and 10.3-fold, respectively. A positive correlation between half-lives of CPA and 4-OH-CPA was found while a significant negative correlation between AUCs of CPA and 4-OH-CPA was detected. In the population analysis, the CYP2B6 G516T variant allele contribution to CPA clearance was about twice as the contribution from the wild type gene while the genotype of CYP2C9 and CYP2C19 did not influence clearance. A negative correlation was observed between bilirubin level and CPA bioactivation.
This study demonstrates for the first time that the presence of the CYP2B6 G516T mutation increases the rate of 4-OH-CPA formation in patients with hematological malignancies. The liver function prior therapy as assessed by s-bilirubin influences CPA metabolism.
据报道，某些癌症患者群体中，环磷酰胺（CPA）的药代动力学存在高度个体间差异。为了更好地理解CPA代谢差异背后的机制，我们研究了血液系统肿瘤患者中CPA及其活性代谢物4-羟基环磷酰胺（4-OH-CPA）的药代动力学。CPA及其活性代谢物的药代动力学与CYP2B6、CYP2C9和CYP2C19的基因型有关。还评估了肝功能对CPA代谢的影响。
本研究招募了29例接受常规CPA剂量（1g/m²）治疗的血液系统恶性肿瘤（MM、ALL或NHL）患者。在CPA治疗前、治疗期间和治疗后采集血样。采用高效液相色谱法测定血浆中CPA和4-OH-CPA的浓度。对患者进行CYP2B6 G516T、CYP2C92、CYP2C93、CYP2C192和CYP2C193等位基因的基因分型。在治疗前测量血清胆红素水平。使用非线性混合效应模型，分别通过个体分析和群体药代动力学方法对数据进行分析。
CPA、4-OHCPA和4-OH-CPA/CPA暴露的个体间变异性分别为5.8倍、3.3倍和10.3倍。发现CPA和4-OH-CPA的半衰期之间呈正相关，而CPA和4-OH-CPA的AUC之间存在显著负相关。在群体分析中，CYP2B6 G516T变异等位基因对CPA清除率的贡献约为野生型基因贡献的两倍，而CYP2C9和CYP2C19的基因型不影响清除率。观察到胆红素水平与CPA生物活化之间呈负相关。
本研究首次证明，CYP2B6 G516T突变的存在增加了血液系统恶性肿瘤患者中4-OH-CPA的形成速率。通过s-胆红素评估的治疗前肝功能影响CPA代谢。
Zotero 插件