Inhibition of human drug metabolizing cytochrome P450 by buprenorphine.
Inhibition of human drug metabolizing cytochrome P450 by buprenorphine.
复制标题
丁丙诺啡对人类药物代谢细胞色素 P450 的抑制作用。
DOI：
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发表时间：
2002
影响因子：
2
通讯作者：
Gohachiro Miyamoto
中科院分区：
文献类型：
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作者：
K. Umehara;Y. Shimokawa;Gohachiro Miyamoto
为了从体外数据预测丁丙诺啡在体内的药物相互作用，研究了丁丙诺啡对人肝微粒体中几种细胞色素P450(CYP)亚型特异性反应的影响。本研究采用了8个CYP催化反应：CYPLA1/2介导的7-乙氧基间苯二酚O-脱乙基化、CYP2A6介导的香豆素7-羟基化、CYP2B6介导的7-苄氧基间苯二酚O-脱苄基化、CYP2C8/9介导的甲苯丁胺甲基化、CYP2C19介导的S-美苯妥因4-羟基化、CYP2D6介导的丁呋喃1‘-羟基化、CYP2E1介导的氯唑沙宗6-羟基化和CYP3A4介导的睾酮6β-羟基化。丁丙诺啡对CYP3A4和CYP2D6催化的反应有强烈的抑制作用，Ki分别为14.7微米和21.4微米。该止痛剂对由CYP1A1/2(Ki=132微米)、CYP2B6(Ki=133微米)、CYP2C19(Ki=146微米)、CYP2C8/9(IC50和GT；300微米)和CYP2E1(IC50和GT；300微米)催化的特异性反应也有微弱的抑制作用，但不能抑制CYP2A6介导的通路。考虑到本研究中获得的Ki值和丁丙诺啡在人血浆中的治疗浓度，丁丙诺啡不会被预测为与其他CYP代谢物引起临床上显著的相互作用。
The effects of buprenorphine, a powerful mixed agonist/antagonist analgesic, on several cytochrome P450 (CYP) isoform specific reactions in human liver microsomes were investigated to predict drug interaction of buprenorphine in vivo from in vitro data. The following eight CYP-catalytic reactions were used in this study: CYPlA1/2-mediated 7-ethoxyresorufin O-deethylation, CYP2A6-mediated coumarin 7-hydroxylation, CYP2B6-mediated 7-benzyloxyresorufin O-debenzylation, CYP2C8/9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated S-mephenytoin 4-hydroxylation, CYP2D6-mediated bufuralol 1'-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated testosterone 6beta-hydroxylation. Buprenorphine strongly inhibited the CYP3A4- and CYP2D6-catalyzed reactions with Ki values of 14.7 microM and 21.4 microM, respectively. The analgesic also weakly inhibited specific reactions catalyzed by CYP1A1/2 (Ki=132 microM), CYP2B6 (Ki=133 microM), CYP2C19 (Ki=146 microM), CYP2C8/9 (IC50>300 microM), and CYP2E1 (IC50>300 microM), but not CYP2A6 mediated pathway. In consideration of the Ki values obtained in this study and the therapeutic concentration of buprenorphine in human plasma, buprenorphine would not be predicted to cause clinically significant interactions with other CYP-metabolized drugs.
影响因子：
4.1
作者：
GUENGERICH, FP;KIM, DH;IWASAKI, M
通讯作者：
IWASAKI, M
影响因子：
4.1
作者：
RETTIE, AE;KORZEKWA, KR;TRAGER, WF
通讯作者：
TRAGER, WF