使用细胞色素P450 3A4表型探针预测伊立替康的药代动力学

Prediction of irinotecan pharmacokinetics by use of cytochrome P450 3A4 phenotyping probes.

作者信息

Mathijssen Ron H J, de Jong Floris A, van Schaik Ron H N, Lepper Erin R, Friberg Lena E, Rietveld Trinet, de Bruijn Peter, Graveland Wilfried J, Figg William D, Verweij Jaap, Sparreboom Alex

机构信息

Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.

出版信息

J Natl Cancer Inst. 2004 Nov 3;96(21):1585-92. doi: 10.1093/jnci/djh298.

DOI:10.1093/jnci/djh298

PMID:15523087

Abstract

BACKGROUND

Irinotecan is a topoisomerase I inhibitor that has been approved for use as a first- and second-line treatment for colorectal cancer. The response to irinotecan is variable, possibly because of interindividual variation in the expression of the enzymes that metabolize irinotecan, including cytochrome P450 3A4 (CYP3A4) and uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). We prospectively explored the relationships between CYP3A phenotype, as assessed by erythromycin metabolism and midazolam clearance, and the metabolism of irinotecan and its active metabolite SN-38.

METHODS

Of the 30 white cancer patients, 27 received at least two treatments with irinotecan administered as one 90-minute infusion (dose, 600 mg) with 3 weeks between treatments, and three received only one treatment. Before the first and second treatments, patients underwent an erythromycin breath test and a midazolam clearance test as phenotyping probes for CYP3A4. Erythromycin metabolism was assessed as the area under the curve for the flux of radioactivity in exhaled CO2 within 40 minutes after administration of [N-methyl-14C]erythromycin. Midazolam and irinotecan were measured by high-performance liquid chromatography. Genomic DNA was isolated from blood and screened for genetic variants in CYP3A4 and UGT1A1. All statistical tests were two-sided.

RESULTS

CYP3A4 activity varied sevenfold (range = 0.223%-1.53% of dose) among patients, whereas midazolam clearance varied fourfold (range = 262-1012 mL/min), although intraindividual variation was small. Erythromycin metabolism was not statistically significantly associated with irinotecan clearance (P = .090), whereas midazolam clearance was highly correlated with irinotecan clearance (r = .745, P<.001). In addition, the presence of a UGT1A1 variant with a (TA)7 repeat in the promoter (UGT1A128) was associated with increased exposure to SN-38 (435 ng x h/mL, 95% confidence interval [CI] = 339 to 531 ng x h/mL in patients who are homozygous for wild-type UGT1A1; 631 ng x h/mL, 95% CI = 499 to 762 ng . h/mL in heterozygous patients; and 1343 ng x h/mL, 95% CI = 0 to 4181 ng x h/mL in patients who are homozygous for UGT1A128) (P = .006).

CONCLUSION

CYP3A4 phenotype, as assessed by midazolam clearance, is statistically significantly associated with irinotecan pharmacokinetics. Evaluation of midazolam clearance combined with UGT1A1*28 genotyping may assist with optimization of irinotecan chemotherapy.

摘要

背景

伊立替康是一种拓扑异构酶I抑制剂，已被批准用于结直肠癌的一线和二线治疗。对伊立替康的反应存在差异，这可能是由于代谢伊立替康的酶（包括细胞色素P450 3A4（CYP3A4）和尿苷二磷酸葡萄糖醛酸基转移酶1A1（UGT1A1））表达的个体间差异所致。我们前瞻性地探讨了通过红霉素代谢和咪达唑仑清除率评估的CYP3A表型与伊立替康及其活性代谢产物SN-38代谢之间的关系。

方法

30例白人癌症患者中，27例接受至少两次伊立替康治疗，每次90分钟静脉输注（剂量600mg），两次治疗间隔3周，3例仅接受一次治疗。在第一次和第二次治疗前，患者接受红霉素呼气试验和咪达唑仑清除试验，作为CYP3A4的表型分析探针。红霉素代谢通过静脉注射[N-甲基-14C]红霉素后40分钟内呼出二氧化碳中放射性通量的曲线下面积进行评估。咪达唑仑和伊立替康通过高效液相色谱法测定。从血液中分离基因组DNA，并筛查CYP3A4和UGT1A1的基因变异。所有统计检验均为双侧检验。

结果

患者间CYP3A4活性相差7倍（范围为剂量的0.223%-1.53%），而咪达唑仑清除率相差4倍（范围为262-1012 mL/min），尽管个体内差异较小。红霉素代谢与伊立替康清除率无统计学显著相关性（P = 0.090），而咪达唑仑清除率与伊立替康清除率高度相关（r = 0.745，P<0.001）。此外，启动子区具有（TA）7重复序列的UGT1A1变异体（UGT1A128）的存在与SN-38暴露增加相关（野生型UGT1A1纯合子患者为435 ng·h/mL，95%置信区间[CI]=339至531 ng·h/mL；杂合子患者为631 ng·h/mL，95%CI = 499至762 ng·h/mL；UGT1A128纯合子患者为1343 ng·h/mL，95%CI = 0至4181 ng·h/mL）（P = 0.006）。