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

本研究对环磷酰胺、达卡巴津、依托泊苷、替加氟、长春新碱、长春新碱、他莫昔芬、阿霉素、阿霉素等抗癌化疗药物在体外多药联合化疗中的药物相互作用、抑制细胞色素P450(CYP)的效力和抑制方式进行了评价。以人肝微粒体为酶来源。在环磷酰胺、依托泊苷、长春新碱和长春新碱四种抗癌药物中，环磷酰胺、依托泊苷、长春新碱和长春新碱对细胞色素P3A4、2C19和2D6介导的药物氧化代谢有较强的抑制作用。在环磷酰胺、依托泊苷和长春新碱等多种药物的联合化疗中，环磷酰胺、依托泊苷和长春新碱三种药物联用或三联用药对细胞色素P3A4和2C19的抑制作用如下：环磷酰胺和依托泊苷对4…的咪达唑仑1‘-羟基化均有抑制作用单用环磷酰胺为19.27%，单用依托泊苷为32.28%。环磷酰胺和长春新碱或依托泊苷和长春新碱合用对咪达唑仑1‘-羟化的抑制作用与环磷酰胺和足叶乙甙合用的抑制作用相似。环磷酰胺、依托泊苷和长春新碱合用对咪达唑仑1‘-羟化的抑制作用与环磷酰胺、依托泊苷和长春新碱合用相当。而环磷酰胺和长春新碱或环磷酰胺和依托泊苷合用则分别抑制了由细胞色素P450_2C19介导的S-美芬妥因4‘-羟基化，分别为对照组的27.27%和25.61%。这种抑制作用与长春新碱或依托泊苷相似。长春新碱和依托泊苷联合应用对S-美苯妥因4‘-羟化反应的抑制作用为对照的39.25%。与长春新碱、长春新碱合用时，长春新碱、长春新碱、长春新碱对S-美芬妥因4‘-羟化的抑制作用为对照的39.67%。长春新碱和长春新碱对细胞色素P3A4、2D6和2C19的抑制方式为：长春花碱竞争性抑制咪达唑仑、S-美苯妥英和丁呋喃1’-羟化，表观Ki值分别为30μM、80μM和36μM。而长春新碱则竞争性抑制细胞色素P3A4、细胞色素P42C19和细胞色素P42D6的活性，其KI值分别为58μM、91μM和87μM。较少

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