Study of the effects of antineoplastic agents on drug metabolizing enzymes and evaluation of its efficacy and safety

抗肿瘤药物对药物代谢酶影响的研究及其有效性和安全性评价

• 批准号: 10672157
• 负责人: YASUHARA Hajime
• 金额: $ 2.05万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10672157/
• 关键词: Antineoplastic agent; Human Liner; CYP; Cytochrome P450; Drug metabolism; in vitro; Inhibition; Interaction; cytochrome P450; ヒト肝ミクロソーム; 代謝阻害; microsome; human liver; ラット

This study had performed to evalute the drug-drug interaction in multi-drug chemotherapy, inhibitory potency and inhibition manner on cytochrome P450 (CYP), in commonly employed antineoplastic agents for the cancer chemotherapy, such as cyclophosphamide, dacarbazine, etoposide, tegafur, vinblastine, vincristine, tamoxifen, doxorubicin and dauorubicin in vitro. Human liver microsome was used as an enzyme source. Among the antineoplastic agents employed in this project, cyclophosphamide, etoposide, vinblastine and vincristine were potently inhibited the CYP3A4, 2C19 and 2D6 mediated oxidative drug metabolism determined by the typical substrates corresponding to each CYP enzyme.In the multi-drug chemotherapy, such as cyclophosphamide, etoposide and vincristine, inhibitory potency by the combination or tripartite therapy of these 3 drugs on CYP3A4 and 2C19 was as follows, CYP3A4, the midazolam 1'-hydroxylation was potently inhibited by existence both of cyclophosphamide and etoposide for 4 … More 1.77% of control value despite cyclophosphamide alone for 19.27% and etoposide alone for 32.28%. Inhibition of midazolam 1'-hydroxylation by concomitant use of cyclophosphamide and vincristine or etoposide and vincristine was similar to the inhibitory effect by cyclophosphamide alone and etoposide alone. Furthermore, inhibitory effect on midazolam 1'-hydroxylation by using cyclophosphamide etoposide and vincristine concurrently was comparable to dual use of these two drugs. On the other hand, S-mephenytoin 4'-hydroxylation, mediated by CYP2C19, was inhibited by concomitant use of cyclophosphamide and vincristine or cyclophosphamide and etoposide for 27.27% and 25.61% of control value, respectively. This inhibitory potency was similar to vincristine or etoposide only. On the other hand, S-mephenytoin 4'-hydroxylation was potently inhibited by dual use of vincristine and etoposide for 39.25% of control. Furthermore, concomitant use of three of the drugs, cyclophosphamide, etoposide and vincristine, S-mephenytoin 4'-hydroxylation was inhibited 39.67% of control value, similar to dual use of vincristine and etoposide.Furthermore, inhibition manner in vinblastine and vincristine on CYP3A4, 2D6 and 2C19 was as follows, vinblastine had inhibited the midazolam 1'-hydroxylation, S-mephenytoin 4'-hydroxylation and bufuralol 1'-hydroxylation competitively and apparent Ki value was 30 μM, 80 μM and 36 μM in CYP3A4, CYP2C19 and CYP2D6, respectively. While, vincristine had inhibited the CYP3A4, CYP2C19 and CYP2D6 activity competitively with apparent Ki value 58 μM, 91μM and 87 μM in CYP3A4, CYP2C19 ad CYP2D6, respectively.In this study had clarify the possibility of the drug-drug interaction with the concomitant administration among the commonly ad antineoplastic agents in routine chemotherapy. Less

本研究对肿瘤化疗中常用的化疗药物环磷酰胺、达卡巴嗪、依托泊苷、替加氟、长春碱、长春新碱、他莫昔芬、阿霉素和柔红霉素进行了体外药物间相互作用的研究，并对细胞色素P450（CYP 450，CYP 450）的抑制作用及抑制方式进行了评价。以人肝微粒体为酶源。在本项目所用的化疗药物中，环磷酰胺、依托泊苷、长春碱和长春新碱对CYP 3A 4、2C 19和2D 6介导的氧化药物代谢具有强效抑制作用，这些药物由每种CYP 3A 4、2C 19和2D 6的典型底物所决定。这3种药物联合或三联治疗对CYP 3A 4和2C 19的抑制效力如下，CYP 3A 4，咪达唑仑1 '-羟基化被环磷酰胺和依托泊苷同时存在的4 ...更多信息 单用环磷酰胺和足叶乙甙分别为对照组的19.27%和32.28%。环磷酰胺和长春新碱或依托泊苷和长春新碱联合使用对咪达唑仑1 '-羟基化的抑制作用与环磷酰胺单药和依托泊苷单药的抑制作用相似。此外，同时使用环磷酰胺、依托泊苷和长春新碱对咪达唑仑1 '-羟基化的抑制作用与这两种药物的双重使用相当。另一方面，环磷酰胺和长春新碱或环磷酰胺和依托泊苷联合使用可抑制CYP 2C 19介导的S-美芬妥英4 '-羟基化，抑制率分别为对照值的27.27%和25.61%。该抑制效力仅与长春新碱或依托泊苷相似。另一方面，长春新碱和依托泊苷联合使用可有效抑制S-美芬妥英4 '-羟基化，抑制率为对照组的39.25%。此外，联合使用环磷酰胺、依托泊苷和长春新碱三种药物，S-美芬妥英4 '-羟基化被抑制为对照值的39.67%，与长春新碱和依托泊苷联合使用相似。此外，长春碱和长春新碱对CYP 3A 4、2D 6和2C 19的抑制方式如下，长春碱抑制咪达唑仑1'-羟基化，在CYP 3A 4、CYP 2C 19和CYP 2D 6中，S-美芬妥英4 '-羟基化和丁呋洛尔1'-羟基化竞争，表观Ki值分别为30 μM、80 μM和36 μM。而长春新碱对CYP 3A 4、CYP 2C 19和CYP 2D 6的活性具有竞争性抑制作用，其表观Ki值分别为58 μM、91μM和87 μM。少

项目成果

Hua Li, Norimitsu Kurata, Yuki Nishimura, Mariko Iwase, Eiji Uchida and Hajime Yasuhara: "The effect of antineoplastic agent cyclophosphamide, etoposide and vincristine on CYP3A4 and CYP2C19 mediated drug metabolism in human liver microsomes"Xenobiotica.

Hua Li、Norimitsu Kurata、Yuki Nishimura、Mariko Iwase、Eiji Uchida 和 Hajime Yasuhara：“抗肿瘤药环磷酰胺、依托泊苷和长春新碱对 CYP3A4 和 CYP2C19 介导的人肝微粒体药物代谢的影响”Xenobiotica。

西村有希、倉田知光、安原一 他: "各種抗癌剤のチトクロームP450に対する阻害効果"日本薬理学会雑誌. 114(4). 59P (1999)

Yuki Nishimura、Tomomitsu Kurata、Hajime Yasuhara等人：“各种抗癌药物对细胞色素P450的抑制作用”日本药理学会杂志114(4)(1999)。

Hua Li, Norimitsu Kurata, Yuki Nishimura, Mariko Iwase, Eiji Uchida and Hajime Yasuhara: "The effect of antineoplastic agent vinblastine and vincristine on CYP3A4, CYP2C19 and CYP2D6 activity in human liver microsomes"Xenobiotica. (Submitted).

Hua Li、Norimitsu Kurata、Yuki Nishimura、Mariko Iwase、Eiji Uchida 和 Hajime Yasuhara：“抗肿瘤剂长春花碱和长春新碱对人肝微粒体 CYP3A4、CYP2C19 和 CYP2D6 活性的影响”Xenobiotica。

Li H., Kurata N., Nishimura Y., Iwase M., Uchida E and Yasuhara H: "Doxorubicin metabolism in liver microsomal cytochrome P450 in rats"Jpn. J. Pharmacol. 79(Suppl I). 157P (1999)

Li H.、Kurata N.、Nishimura Y.、Iwase M.、Uchida E 和 Yasuhara H：“大鼠肝微粒体细胞色素 P450 中的多柔比星代谢”Jpn。

Li H., Kurata N., Nishimura Y., Iwase M., Uchida E and Yasuhara H: "The effect of antineoplastic agent vinblastine and vincristine on CYP3A4, CYP2C19 and CYP2D6 activity in human liver microsome"Jpn. J. Pharmacol. 82(Suppl I). in press (2000)

Li H.、Kurata N.、Nishimura Y.、Iwase M.、Uchida E 和 Yasuhara H：“抗肿瘤剂长春花碱和长春新碱对人肝微粒体 CYP3A4、CYP2C19 和 CYP2D6 活性的影响”Jpn。