联合用药对硫替派转化为替派及硫替派巯基尿酸生物转化的影响。

Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate.

作者信息

van Maanen M J, Huitema A D, Beijen J H

机构信息

Utrecht University, Department of Pharmaceutical Analysis, The Netherlands.

出版信息

Anticancer Res. 2000 May-Jun;20(3A):1711-6.

PMID:10928097

Abstract

BACKGROUND

The combination of cyclophosphamide, thioTEPA and carboplatin is used in our Institute for the treatment of breast or germ cell cancer. ThioTEPA inhibits the bioactivation of cyclophosphamide, and platinum drugs are known to interfere with the hepatic metabolism of several anticancer drugs. Of the co-administered drugs to prevent unwanted side effects, some are enzyme inducers, cytochrome P450 inhibitors or substrates. The aim of this study was to investigate the influence of co-medicated drugs on the biotransformation of thioTEPA.

METHODS

The possible inhibition of the metabolism of thioTEPA to TEPA was investigated in human microsomes. Influences on the conversion of thioTEPA to monoglutathionylthioTEPA, was studied by the incubation of thioTEPA with glutathione and glutathione S-transferase.

RESULTS

No inhibition of the metabolism of thioTEPA to form TEPA was observed for cyclophosphamide and carboplatin, or any other co-medicated drug (ciproflocaxin, amphotericin B, itraconazol, fluconazol, ondansetron, dexamethasone, granisetron, aciclovir, ranitidine, lorazepam). The conversion of thioTEPA to monoglutathionylthioTEPA was inhibited by cyclophosphamide, itraconazol, amphotericin B and ondansetron with IC50 values of 58, 256, 55 and 40 mM, respectively, which are far higher than therapeutic drug levels.

CONCLUSION

No clinically relevant drug-drug interactions occur in the CTC regimen as applied in our Institute.

摘要

背景

我院使用环磷酰胺、噻替派和卡铂联合治疗乳腺癌或生殖细胞癌。噻替派可抑制环磷酰胺的生物活化，且已知铂类药物会干扰多种抗癌药物的肝脏代谢。在联合使用的预防不良反应的药物中，有些是酶诱导剂、细胞色素P450抑制剂或底物。本研究的目的是调查联合用药对噻替派生物转化的影响。

方法

在人微粒体中研究了对噻替派代谢为替派的可能抑制作用。通过将噻替派与谷胱甘肽和谷胱甘肽S-转移酶孵育，研究对噻替派转化为单谷胱甘肽基噻替派的影响。

结果

未观察到环磷酰胺、卡铂或任何其他联合用药（环丙沙星、两性霉素B、伊曲康唑、氟康唑、昂丹司琼、地塞米松、格拉司琼、阿昔洛韦、雷尼替丁、劳拉西泮）对噻替派代谢形成替派有抑制作用。环磷酰胺、伊曲康唑、两性霉素B和昂丹司琼对噻替派转化为单谷胱甘肽基噻替派有抑制作用，IC50值分别为58、256、55和40 mM, 远高于治疗药物水平。