与ABCG2 421C>A基因型相关的地氟莫特康药代动力学。

Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype.

作者信息

Sparreboom Alex, Gelderblom Hans, Marsh Sharon, Ahluwalia Ranjeet, Obach Rosendo, Principe Paola, Twelves Chris, Verweij Jaap, McLeod Howard L

机构信息

Medical Oncology Clinical Research Unit, National Cancer Institute, Bethesda, MD 20892, USA.

出版信息

Clin Pharmacol Ther. 2004 Jul;76(1):38-44. doi: 10.1016/j.clpt.2004.03.003.

DOI:10.1016/j.clpt.2004.03.003

PMID:15229462

Abstract

OBJECTIVE

The adenosine triphosphate-binding cassette transporter ABCG2 (breast cancer resistance protein [BCRP]) functions as an efflux transporter for many drugs, including the topoisomerase I inhibitor diflomotecan, and is expressed at high levels in the intestine and liver. We performed an exploratory analysis to evaluate the effects of the natural allelic variant ABCG2 421C>A on the pharmacokinetics of diflomotecan.

METHODS

The drug was administered to 22 adult white patients with cancer as a 20-minute infusion (dose, 0.10-0.27 mg), followed 2 weeks later by an oral solution (dose, 0.10-0.35 mg).

RESULTS

The ABCG2 421C>A genotype significantly affected the pharmacokinetics of diflomotecan; in 5 patients heterozygous for this allele, plasma levels after intravenous drug administration were 299% (P =.015) of those in 15 patients with wild-type alleles, at mean values of 138 ng x h/mL x mg(-1) (95% confidence interval, 11.3-264 ng x h/mL x mg(-1)) versus 46.1 ng x h/mL x mg(-1) (95% confidence interval, 25.6-66.7 ng x h/mL x mg(-1)), respectively. Diflomotecan levels were not significantly influenced by 11 known variants in the ABCB1, ABCC2, cytochrome P450 (CYP) 3A4, and CYP3A5 genes.

CONCLUSION

These findings provide the first evidence linking variant ABCG2 alleles to altered drug exposure and suggest that interindividual variability in substrate drug effects might be influenced, in part, by ABCG2 genotype.

摘要

目的

三磷酸腺苷结合盒转运体ABCG2（乳腺癌耐药蛋白[BCRP]）作为多种药物的外排转运体发挥作用，包括拓扑异构酶I抑制剂地氟莫特坎，且在肠道和肝脏中高表达。我们进行了一项探索性分析，以评估天然等位基因变体ABCG2 421C>A对地氟莫特坎药代动力学的影响。

方法

将该药物以20分钟输注的方式给予22例成年白人癌症患者（剂量为0.10 - 0.27 mg），2周后给予口服溶液（剂量为0.10 - 0.35 mg）。

结果

ABCG2 421C>A基因型显著影响地氟莫特坎的药代动力学；在5例该等位基因杂合的患者中，静脉给药后的血浆水平是15例野生型等位基因患者的299%（P = 0.015），平均值分别为138 ng·h/mL·mg⁻¹（95%置信区间，11.3 - 264 ng·h/mL·mg⁻¹）和46.1 ng·h/mL·mg⁻¹（95%置信区间，25.6 - 66.7 ng·h/mL·mg⁻¹）。地氟莫特坎水平不受ABCB1、ABCC2、细胞色素P450（CYP）3A4和CYP3A5基因中11种已知变体的显著影响。