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

本研究对肿瘤化疗中常用的抗肿瘤药物环磷酰胺、达卡巴嗪、依托泊苷、替加富、长春花碱、长春新碱、他莫昔芬、阿霉素、道柔比星等多药化疗中药物间的相互作用、对细胞色素P450 （CYP）的抑制效力和抑制方式进行了体外评价。以人肝微粒体为酶源。在本项目使用的抗肿瘤药物中，环磷酰胺、依托泊苷、长春花碱和长春新碱均能有效抑制CYP3A4、2C19和2D6介导的氧化药物代谢，这是由各CYP酶对应的典型底物决定的。在环磷酰胺、依托泊苷、长春新碱等多药化疗中，3种药物联合或三联治疗对CYP3A4和2C19的抑制效力如下：环磷酰胺和依托泊苷同时存在时，CYP3A4的咪达唑仑1′-羟基化作用被有效抑制，抑制率为1.77%，单用环磷酰胺19.27%，单用依托泊苷32.28%。环磷酰胺联合长春新碱或依托泊苷联合长春新碱对咪达唑仑1′-羟基化的抑制作用与单用环磷酰胺和依托泊苷的抑制作用相似。此外，环磷酰胺依托泊苷和长春新碱同时使用对咪达唑仑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，环磷酰胺与长春新碱或环磷酰胺与依托泊苷联用对CYP2C19介导的s -甲苯托因4′-羟基化的抑制作用分别为对照值的27.27%和25.61%。这种抑制效力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双重使用对s -甲苯妥英4′-羟基化的抑制作用为39.25%。同时使用环磷酰胺、依托泊苷和长春新碱3种药物，s -甲苯托英4′-羟基化作用被抑制值为对照值的39.67%，与长春新碱和依托泊苷双用相似。长春花碱和长春新碱对CYP3A4、2D6和2C19的抑制方式如下，长春花碱对咪达唑仑1′-羟基化、s -甲苯妥英4′-羟基化和丁腈醇1′-羟基化具有竞争性抑制作用，CYP3A4、CYP2C19和CYP2D6的表观Ki值分别为30 μM、80 μM和36 μM。长春新碱对CYP3A4、CYP2C19和CYP2D6具有竞争性抑制作用，其Ki值分别为58 μM、91μM和87 μM。本研究阐明了常规化疗中常用和抗肿瘤药物同时使用时药物-药物相互作用的可能性。少

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