Effect of danshen extract on the activity of CYP3A4 in healthy volunteers

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Many cytochrome P450 mediated interactions have been reported between drug and herbal medicines. In particular, CYP3A4 is known to play a critical role in several clinically relevant herb-drug interactions. Midazolam has been reported to be one of the preferred in vivo CYP3A probes.• It has been reported that the lipophilic components of danshen could induce CYP3A in C57BL/6J mice, that cryptotanshinone and tanshinone IIA of danshen extract could activate human PXR and consequently induce the expression of the CYP3A4 gene. WHAT THIS STUDY ADDS• Co-administration of multiple doses of danshen tablets caused an increase in apparent oral clearance of midazolam by 35.4%, a corresponding decline in Cmax by 31.1% and a decline in AUC(0,•) by 27.0% in human volunteers. The t1/2 of midazolam and 1-hydroxymidazolam were not changed, and the Cmax and AUC(0,•) ratio of midazolam to 1-hydroxymidazolam were not affected. The results suggested that multiple dose administration of danshen tablets could induce CYP3A4 in the gut, thereby increasing the clearance of midazolam. Therefore, caution should be taken when danshen products containing lipophilic components are used in combination with therapeutic drugs metabolized by CYP3A. AIMSTo assess the effect of danshen extract on CYP3A4 activity using midazolam as an in vivo probe. METHODSA sequential, open-label, two-period pharmacokinetic interaction study design was used to compare midazolam pharmacokinetic parameters before and after 14 days of administration of danshen tablets. Twelve healthy volunteers received a single oral dose (15 mg) of midazolam followed by danshen tablets (four tablets orally, three times a day) for 14 days. On the last day of the study they received four danshen tablets with a 15 mg midazolam tablet and plasma concentrations of midazolam and its corresponding metabolite 1-hydroxylmidazolam were measured prior to and after the administration of danshen tablets periodically for 12 h. RESULTSThe 90% confidence intervals of Cmax, t1/2, CL/F and AUC(0,•) of midazolam before and after administration of danshen tablets were (0.559, 0.849), (0.908, 1.142), (1.086, 1.688) and (0.592, 0.921), respectively; and those of Cmax, t1/2 and AUC(0,•) of 1-hydroxylmidazolam after vs. before administration of danshen tablets were (0.633, 0.923), (0.801, 1.210) and (0.573, 0.980), respectively. Ratios of geometric LS means of Cmax(1OHMid) : Cmax(Mid) and AUCmax(1OHMid) : AUCmax(Mid) (after vs. before 14-day danshen) were 1.072 and 1.035, respectively. CONCLUSIONSOur findings suggest that multiple dose administration of danshen tablets may induce CYP3A4 in the gut. Accordingly, caution should be taken when danshen products are used in combination with therapeutic drugs metabolized by CYP3A. Danshen, the dried root of Salvia miltiorrhiza, has been used for more than 2000 years in China for the treatment of numerous ailments [6]. Danshen extract contains both hydrophilic components (danshensu, protocatechuic aldehyde and salvianolic a...

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“…Case reports have highlighted the possibility of interactions between warfarin and danshen, resulting in an increased anticoagulant effect [41,42,43,44]. A pharmacokinetic mechanism seems unlikely since danshen has been shown to induce intestinal CYP3A4 in 14 healthy volunteers [45]. …”

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“…(35,36) However, in vivo and ex vivo studies have found that danshen components induce CYP3A4 in humans, and CYP1A, 2C and 3A in mice. (37,38) …”