Backman J T, Mäenpää J, Belle D J, Wrighton S A, Kivistö K T, Neuvonen P J
Department of Clinical Pharmacology, University of Helsinki, Finland.
Clin Pharmacol Ther. 2000 Apr;67(4):382-90. doi: 10.1067/mcp.2000.105756.
Tangeretin is a flavonoid that stimulates the catalytic activity of cytochrome P450 3A4 (CYP3A4) and is found in high levels in tangerine juice.
The effect of tangeretin on hydroxylation of midazolam, a CYP3A4 probe, was examined in vitro with human liver microsomes and recombinant CYP3A4. In addition, the effect of tangerine juice on the pharmacokinetics and pharmacodynamics of orally administered midazolam (15 mg) and its active 1'-hydroxymetabolite was studied in a randomized crossover study in eight healthy volunteers.
In microsomes from three human livers, tangeretin (1 to 100 micromol/L) increased 1'-hydroxymidazolam formation (12.5 micromol/L midazolam) by up to 212%. In complementary deoxyribonucleic acid-expressed CYP3A4, a 52% stimulation of midazolam 1'-hydroxylation was reached at 50 micromol/L tangeretin with no effect on midazolam 4-hydroxylation. In the pharmacokinetic-pharmacodynamic study, 200 mL tangerine juice reduced the area under the concentration versus time curve to 1.5 hours [AUC(O-1.5h)] of midazolam and 1'-hydroxymidazolam by 39% and 46%, respectively, and prolonged the time to reach peak concentration (P < .05) without affecting the total AUC values, elimination half-life values, or AUC ratios (1'-hydroxymidazolam/midazolam). These findings are consistent with a small delay in the absorption of midazolam and lack of effect on midazolam 1'-hydroxylation. Accordingly, tangerine juice slightly postponed the maximum pharmacodynamic effects of midazolam (P < .05).
Tangeretin is a potent regioselective stimulator of midazolam 1'-hydroxylation by human liver microsomes and complementary deoxyribonucleic acid-expressed CYP3A4. However, tangerine juice is unlikely to have any appreciable effect on CYP3A4 in humans. Further studies are required to assess whether in vitro stimulators of CYP3A4 can influence drug metabolism in vivo.
陈皮苷是一种黄酮类化合物，可刺激细胞色素P450 3A4（CYP3A4）的催化活性，且在橙汁中含量很高。
在体外用人肝微粒体和重组CYP3A4研究陈皮苷对CYP3A4探针咪达唑仑羟基化的影响。此外，在一项随机交叉研究中，对8名健康志愿者口服咪达唑仑（15毫克）及其活性1'-羟基代谢物的药代动力学和药效学进行了研究。
在来自三个人肝脏的微粒体中，陈皮苷（1至100微摩尔/升）使1'-羟基咪达唑仑的生成量（12.5微摩尔/升咪达唑仑）增加了212%。在互补脱氧核糖核酸表达的CYP3A4中，50微摩尔/升的陈皮苷使咪达唑仑1'-羟基化增加了52%，而对咪达唑仑4-羟基化没有影响。在药代动力学-药效学研究中，200毫升橙汁使咪达唑仑和1'-羟基咪达唑仑的浓度-时间曲线下面积至1.5小时[AUC（0-1.5小时）]分别降低了39%和46%，并延长了达到峰值浓度的时间（P<.05），而不影响总AUC值、消除半衰期值或AUC比值（1'-羟基咪达唑仑/咪达唑仑）。这些发现与咪达唑仑吸收略有延迟且对咪达唑仑1'-羟基化无影响一致。因此，橙汁略微推迟了咪达唑仑的最大药效学效应（P<.05）。
陈皮苷是一种有效的人肝微粒体和互补脱氧核糖核酸表达的CYP3A4对咪达唑仑1'-羟基化的区域选择性刺激剂。然而，橙汁不太可能对人体中的CYP3A4有任何明显影响。需要进一步研究以评估CYP3A4的体外刺激剂是否能影响体内药物代谢。
