|Budget Amount *help
¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 1999 : ¥1,200,000 (Direct Cost : ¥1,200,000)
Fiscal Year 1998 : ¥2,000,000 (Direct Cost : ¥2,000,000)
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
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