PDF(Pubmed)
Abstract：
The dose dependence of the effect of enzyme inducers and the effect of the combined administration of two inducers that exert their effect via the same induction pathway (pregnane X receptor) have not been well studied. Using oral midazolam microdoses (30 μg), we have investigated CYP3A4 induction by St. John\'s wort (SJW) in 11 healthy volunteers using low (300 mg/day containing 7.48 mg hyperforin), therapeutic (900 mg/day), and supratherapeutic doses of SJW (1800 mg/day) for 14 days. SJW was then co-administered with rifampin (600 mg/day) for a further 7 days to evaluate the effect of the combined administration of two inducers. In addition, intravenous midazolam microdoses (10 μg) were administered before SJW, at SJW 1800 mg/day, and during administration of the two inducers to assess the hepatic contribution to total induction (semi-simultaneous administration). Administration of SJW increased oral midazolam clearance 1.96-fold (300 mg/day), 3.86-fold (900 mg/day), and 5.62-fold (1800 mg/day), and 17.5-fold after the addition of rifampin. Concurrently, the clearance of intravenous midazolam increased 2.05-fold (1800 mg/day) and 2.93-fold (SJW + rifampin). These results show that rifampin significantly enhances the induction of the highest SJW doses both hepatically and overall and suggest that these metabolic effects occur predominantly in the gut. These findings also suggest that in drug interactions involving strong and moderate enzyme inducers, the perpetrator effects of the strong inducer are decisive for the interaction.
摘要：
酶诱导剂的作用的剂量依赖性和通过相同的诱导途径（孕烷X受体）发挥其作用的两种诱导剂的联合给药的作用尚未得到很好的研究。使用口服咪达唑仑微剂量（30μg），我们已经研究了CYP3A4诱导的圣约翰草（SJW）在11名健康志愿者使用低（300毫克/天，含7.48毫克高富素），治疗性（900毫克/天），和SJW的超治疗剂量（1800毫克/天）14天。然后将SJW与利福平(600mg/天)共同施用另外7天,以评价两种诱导剂的组合施用的效果。此外,在SJW之前静脉注射咪达唑仑微剂量（10μg），在SJW1800毫克/天，以及在施用两种诱导剂期间评估肝脏对总诱导的贡献(半同时施用)。服用SJW使口服咪达唑仑清除率增加1.96倍（300mg/天），3.86倍（900毫克/天），和5.62倍（1800毫克/天），加入利福平后的17.5倍。同时,静脉注射咪达唑仑的清除率分别增加2.05倍(1800mg/天)和2.93倍(SJW+利福平).这些结果表明，利福平在肝和整体上均显着增强了最高SJW剂量的诱导，并表明这些代谢作用主要发生在肠道中。这些发现还表明，在涉及强和中等酶诱导剂的药物相互作用中，强诱导剂的加害者效应对相互作用是决定性的。
